Diagnostic tools assessing airway remodelling in asthma

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Tuncel, P. Uysal, A.B. Hocaoglu, D.O. Erge, O. Karaman, N. Uzuner" "autores" => array:6 [ 0 => array:2 [ "nombre" => "T." "apellidos" => "Tuncel" ] 1 => array:2 [ "nombre" => "P." "apellidos" => "Uysal" ] 2 => array:2 [ "nombre" => "A.B." "apellidos" => "Hocaoglu" ] 3 => array:2 [ "nombre" => "D.O." "apellidos" => "Erge" ] 4 => array:2 [ "nombre" => "O." "apellidos" => "Karaman" ] 5 => array:2 [ "nombre" => "N." 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"apellidos" => "Reche" ] 2 => array:2 [ "nombre" => "M.A." "apellidos" => "Padial" ] 3 => array:2 [ "nombre" => "T." "apellidos" => "Valbuena" ] 4 => array:2 [ "nombre" => "C." "apellidos" => "Pascual" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Allergy Department, Hospital Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "IntroductionAsthma is an inflammatory disease of lower airways characterised by the presence of airway inflammation, reversible airflow obstruction and airway hyperresponsiveness and, as lately described, alterations on the normal structure of the airways.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The presence of these alterations, known as remodelling, has been postulated to play an important role in the pathogenesis of asthma, and the absence of treatment of these alterations may be a lack in the prognosis of asthma patients. Remodelling is characterised by the presence of metaplasia of mucous glands, thickening of the lamina reticularis, increased angiogenesis, subepithelial fibrosis and smooth muscle hypertrophy/hyperplasia.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>Several immune cells have been related with the pathogenesis of airway remodelling, including T cells, eosinophils, mast cells, fibroblasts and other epithelial cells.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> These cells could be evaluated by different invasive methods (including bronchial biopsies, analysis of bronchoalveolar lavage solid phase, etc.) or non-invasive methods (i.e. induced sputum solid phase analysis). Pathogenesis of airway remodelling is also related with structural alterations of the airway,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> which could be diagnosed by imaging techniques (i.e. high resolution computerised tomography) and invasive methods such as bronchial biopsies. The presence of different pro-inflammatory mediators and cytokines involved in remodelling<a class="elsevierStyleCrossRef" href="#bib0015">3</a> could be evaluated through invasive methods (e.g. detecting mediators in bronchial biopsies or bronchoalveolar lavage), as well as indirect methods (including analysis of induced sputum liquid phase). Finally, asthma has always been related with functional alterations, evaluation of bronchial hyperresponsiveness and lung function test could bring us important information about the level of bronchial remodelling.Early diagnosis of airway remodelling will play an important role in the near future of asthma; several techniques are being optimised at present to achieve a suitable diagnosis. All these techniques are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Remodelling physiopathologyRemodelling is characterised, as previously described, by the presence of different structural alterations such as metaplasia of mucous glands, thickening of the lamina reticularis, increased angiogenesis, subepithelial fibrosis and smooth muscle hypertrophy/hyperplasia.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> All these structural modifications are caused by different immunological-related mediators or cellular mechanisms. Structural alterations are accompanied by functional changes, and both sorts of changes are obviously related. Regarding these aspects it is essential to introduce the epithelial mesenchymal trophic unit (EMTU) concept, described by Plopper and Evans.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The EMTU is a concept linked to the existence of an attenuated fibroblast layer between epithelial and mesenchymal cells. These fibroblasts are able to differentiate into myofibroblasts, as a response to some local stimuli, and secrete different cellular mediators and proteins known as extracellular matrix (ECM). ECM is a dynamic structure that influences epithelium cells, smooth muscle cells, blood vessels and neural terminations. Activated EMTU is related with the persistence of airway inflammation, the abnormal reparation of damaged epithelium and fibroblasts proliferation, creating a microenvironment similar to a chronic wound in the asthmatic airway. In short, EMTU is referred to different airway structures, cells layers and secreted mediators that control airway inflammation and repair process.It is essential to understand how EMTU controls the different processes involving airway structure, and the important role that ECM plays in airway remodelling. After an acute epithelial injury (i.e. tobacco smoke or allergen exposure, viruses), an increment in the number of fibroblasts occurs, accompanied by an increase in the ECM production (including proteins like fibronectin, tenascin and I–III–V collagen) that alters smooth muscle function.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> All these changes are regulated by several cytokines and pro-fibrotic mediators, such as transforming growth factor (TGF)-β and epidermal growth factor (EGF) mainly, resulting in an increment of subepithelial fibrosis. Simultaneously, increased angiogenesis and vascular permeability promoted by vascular endothelial growth factors (VEGFs) secreted by smooth muscle cells,<a class="elsevierStyleCrossRef" href="#bib0035">7</a> induce airway oedema and inflammatory cells recruitment (mainly eosinophils and mast cells). All these changes induce smooth muscle and epithelial cell proliferation, with an increased production of different cytokines like interleukin 1 (IL-1), IL-5, IL-13 or tumour necrosis factor-α (TNF-α), lipidic mediators like leukotriene D4 (LTD4) or prostaglandine E2 (PGE2) and growth factors like EGF, TGF-β, platelet derived growth factors (PDGFs) or VEGFs (<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>). Production of all these mediators provides a source of chronic inflammation and fibrosis that causes all the structural alterations mentioned above, leading the asthmatic airway to a remodelling process.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Invasive methodsSeveral years ago specimens obtained from post-mortem studies brought us the first information about structural alterations in asthmatic lungs. Invasive methods of analysing bronchial morphology are able to quantify remodelling alterations in a direct way, showing structural modifications and bronchial wall cell infiltration present in bronchial specimens. These methods allow evaluating inflammatory and epithelial cells, as well as cytokines, inflammatory and pro-fibrotic mediators that are present in subjects in different moments of their process. Invasive methods are usually employed in investigational studies and have been used to evaluate evolution of asthma and response to treatment. The most commonly employed invasive methods, including bronchial biopsies and bronchoalveolar lavage, will be described below.Bronchial biopsiesBronchial biopsy (BB) was first employed to evaluate asthma severity in the early 1960s, but it was in the 1990s when BB became extensively used to assess airway remodelling in asthmatic patients.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> BB allows evaluating structural and morphological changes in bronchial specimens with the lack of analysing not the entire airway wall, but superficial airway layers. At least, five to eight specimens should be obtained for a correct diagnosis.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Two different methods for obtaining BB have been usually employed: endobronchial biopsy (EBB) and transbronchial biopsy (TBB). Both techniques should be performed by specialists in a hospital environment using flexible bronchoscopy. EBB makes it possible to obtain large airway specimens, while TBB permits to obtain distal airway and alveolar tissue specimens. EBB presents fewer complications than TBB, but information regarding airway remodelling is more extensive when TBB is employed, this is due to the capability of analysing distal airway remodelling.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> Both biopsy techniques have been shown to give similar results when compared with surgically obtained specimens.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>BB has been employed in several studies to assess airway remodelling, some of them employing EBB<a class="elsevierStyleCrossRefs" href="#bib0060">12–14</a> and another TBB,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and some studies have even employed and compared both techniques.<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a> Most of these studies have analysed the presence of inflammatory cells, fibroblasts and inflammatory mediators in bronchial specimens, but BB has also been employed to elucidate asthmatic patients’ response to corticosteroid treatment.<a class="elsevierStyleCrossRefs" href="#bib0090">18–20</a> BB obtained before and after corticosteroid treatment gives important information about the airway structural modifications produced by these drugs. The use of BB has been implemented in the past years, regarding different aspects of asthma pathogenesis, and BB has been employed, for example, to evaluate the relationship between airway remodelling and airway hyperresponsiveness<a class="elsevierStyleCrossRef" href="#bib0105">21</a> or between airway remodelling and inflammation.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>In short, BB has probably become the most useful technique to evaluate airway remodelling and its relationship with other aspects of asthma pathology, such as airway inflammation or treatment response. Even though BB is undoubtedly useful, it also presents some disadvantages such as the risk of severe complications (like bleeding or pneumothorax); the difficulty to obtain suitable specimens; or the requirement of trained personal to perform flexible bronchoscopy.Bronchoalveolar lavageBronchoalveolar lavage (BAL) could be considered a complementary tool of bronchial biopsies, since both kinds of samples should be obtained by bronchoscopy techniques. BAL could be obtained in the same intervention as bronchial biopsies, and could give us important information about cells and airway remodelling-related markers, without biopsy-associated risks. The BAL technique consists in instilling saline solution, through the instrumentation channel of a bronchoscope, into a segmental or subsegmental bronchus. After saline instilling, this solution is then aspirated into a sterile container. Specimens obtained should be processed and centrifuged to obtain a solid and a liquid phase.As well as biopsy, BAL makes it possible to evaluate inflammatory cells related to airway remodelling in BAL solid phase obtained after centrifugation. Different articles<a class="elsevierStyleCrossRefs" href="#bib0115">23–25</a> have shown elevated levels of T regulatory cells, fibrocytes and neutrophils in BAL from asthmatic subjects, and its relationship with airway inflammation and remodelling. But, BAL has also been employed to analyse remodelling-related markers, for these studies the liquid phase of BAL was obtained after centrifugation. Different markers, such as transforming growth factor-β1 (TGF-β1) or insulin-like growth factor binding protein-3 (IGFBP3) presented modified levels in the liquid phase of BAL, when compared with control subjects’ ones.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a>In resume, BAL presents advantages like the possibility of obtaining samples simultaneously to bronchial biopsies, evaluating inflammatory cells or remodelling-related mediators, and evaluation simplicity. On the other hand, BAL disadvantages lies in the difficulty to obtain samples (bronchoscopy is required) and the limited amount of epithelium and epithelial underlying layers cells obtained.Non-invasive methodsIn the last 50 years clinical practice has tried to reduce the use of invasive techniques for diagnosing airway pathologies. Technical and clinical difficulties involving direct or invasive methods have promoted the development of different non-invasive methods to evaluate the presence of airway remodelling in asthmatic patients. Non-invasive methods are based in the study of different inflammatory cells and mediators related with airway remodelling obtained from sputum, bronchoalveolar lavage and other systemic fluids, or from breath exhaled. Non-invasive methods bring information about clinical features as well as investigational data of evolution and modification of asthmatic disease.Induced sputumInduced sputum (IS) first protocol was described by Bickerman in 1958<a class="elsevierStyleCrossRef" href="#bib0140">28</a>; after this description, several studies have demonstrated the usefulness of IS when diagnosing different respiratory diseases.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Sputum induction consists in the inhalation of increasing concentrations of hypertonic saline (3%, 4% and 5%) during 10min, and obtaining the sputum produced in a sterile container. Solid sputum material is separated from saliva, treated with 0.1% dithiothreitol (DTT) and mucus is removed by filtration. Material obtained is centrifuged to separate liquid and solid phase.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> IS analysis, after processing and centrifugation of samples, permits to evaluate levels of inflammatory cells, lipidic mediators and cytokines in a safe way, even in moderate or severe asthma.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Flow cytometry or cytospin analysis and microscopical cell count, performed in solid phase of IS, make it possible for investigators to establish a cellular pattern involving respiratory pathologies, including asthma airway remodelling. For example, Kaminska et al.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> tried to identify the inflammatory cell patterns of airway remodelling in different subtypes of severe asthma; eosinophils count performed in IS showed to not be able to identify such different subtypes. Eosinophils count in IS, together with exhaled nitric oxide and remodelling-related markers like interleukins, has also been employed in children to identify two different phenotypes of moderate asthma.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> Recently, Broekema et al.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> employed IS to evaluate differences in airway remodelling between actually asthmatic patients and patients with clinical or complete asthma remission. Finally, IS solid phase has also been demonstrated to be useful when evaluating airway remodelling response to corticosteroid treatment in asthmatic patients.<a class="elsevierStyleCrossRef" href="#bib0175">35</a>The liquid phase of IS has been employed to evaluate levels of pro-inflammatory markers and cytokines involving airway remodelling. This is probably the most known featuring of IS, and it has been defined as a relevant technique when evaluating different remodelling markers such as TGF-β1, vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) and others.<a class="elsevierStyleCrossRefs" href="#bib0180">36–38</a> But analysis of the liquid phase of IS, has also been demonstrated as a useful tool to evaluate airway remodelling differences between different coughing pathologies, like asthma and eosinophilic bronchitis.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>In summary, due to its different applications; the fact that it is easy to obtain; and the absence of risk for patients, IS has become, probably, the most useful technique to evaluate airway remodelling in a non-invasive manner.Exhaled nitric oxideExhaled nitric oxide (FeNO) has been related with the presence of inflammation in bronchi of asthmatic patients,<a class="elsevierStyleCrossRef" href="#bib0200">40</a> and it has been also proposed as an efficient technique to evaluate asthmatic exacerbations<a class="elsevierStyleCrossRef" href="#bib0205">41</a> and asthmatic response to treatment.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> The method of FeNO measuring is simple and is performed by breathing through a chemiluminescence analyser for about 6s, according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines.Several studies have suggested that FeNO could represent an easy and accessible tool to assess airway remodelling in adults as well as in children suffering asthma. Ketai et al.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> demonstrated that FeNO levels were elevated during acute asthma exacerbations, related with bronchial wall area assessed by high-resolution computed tomography, but these elevated levels did not persist when acute exacerbations were treated. When the FeNO and airway remodelling relationship has been measured in children<a class="elsevierStyleCrossRef" href="#bib0220">44</a> a positive correlation with FeNO has been demonstrated. This correlation has also been shown when adolescents were evaluated,<a class="elsevierStyleCrossRef" href="#bib0225">45</a> and elevated levels of FeNO were related with AHR and airway remodelling in children ≥12 years of age.Although FeNO is well related with bronchial inflammation and seems to be linked to airway remodelling, this last relationship still remains unclear. Most studies that have been performed evaluating FeNO levels present a lack of dispersion referring to age of patients, severity of asthma and methods used to evaluate remodelling. More specific studies, especially regarding severity of asthma, are necessary to assure that FeNO is a useful tool to evaluate airway remodelling.Exhaled breath condensateNot many articles regarding the use of exhaled breath condensate (EBC) in the study of airway remodelling have been published. Despite the recent use of EBC to establish the existence of airway remodelling in asthmatic patients, it seems to be a useful tool. To obtain EBC, a refrigerating exhaled breath circuit should be used. Patients have to breathe through this circuit at tidal volume for 10min and samples obtained should be processed before analysing.Lex et al.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> demonstrated the relationship between levels of cystenyl leukotrienes (cysLTs), previously described as a marker for airway remodelling,<a class="elsevierStyleCrossRef" href="#bib0235">47</a> measured in EBC, and airway remodelling, assessed as reticular basement membrane thickening in biopsies obtained in children. Another study has described the relationship between Endotelin-1 (ET-1), another marker implicated in airway remodelling, measured in EBC, with different degrees of asthma severity in adult asthmatic patients.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Evaluation of EBC levels of remodelling-related markers has been demonstrated as a valid technique when evaluating remodelling, although more studies are necessary to assure this point.Peripheral blood, urine, saliva and other biological fluidsThe analysis of airway remodelling-related mediators in different peripheral fluids seems to be an economical and easy way to evaluate airway remodelling levels in asthmatic patients. Peripheral fluids have been employed in murine models to evaluate these remodelling markers and, in the past years, have been developed in humans. MMP-9 levels in asthmatic patients’ blood have been evaluated in different studies,<a class="elsevierStyleCrossRefs" href="#bib0245">49,50</a> showing contradictory results. Recently, another study performed in humans,<a class="elsevierStyleCrossRef" href="#bib0255">51</a> has evaluated levels of Fibulin-1 (a secreted glycoprotein that assists in stabilising extracellular matrix) in serum of asthmatic patients and healthy volunteers; Fibulin-1 levels were significantly increased in asthmatic patients.Further studies are necessary, involving different peripheral fluids, cells and related markers, to establish the relevance of these techniques when evaluating airway remodelling.Imaging techniquesRecent advances in imaging techniques provide asthma with a new course to evaluate the presence of remodelling in bronchial airway. Improvement in computerised tomography (CT) resolution, the employing of new collimation techniques and new reconstruction algorithms bring imaging techniques a leading role in asthma evaluation. Moreover, improvements in endoscopic ultrasonography techniques, including smaller probes and better resolution images, complete the advances that make the indirect evaluation of airway remodelling through imaging techniques possible.High resolution computerised tomographyBronchial wall thickening has been described as one of the most important findings in asthma patients but not in healthy subjects,<a class="elsevierStyleCrossRef" href="#bib0260">52</a> but its evaluation required obtaining bronchial biopsies. To solve the lack of obtaining bronchial specimens, computerised tomography (CT) and especially high resolution CT (HRCT) have been employed in several trials as a bloodless method to evaluate bronchial airway structural changes. In contrast, HRCT presents high radiation exposition and an elevated cost as principal objections to its extended use. Due to these disadvantages, at present the CT technique is limited to investigational trials and severe asthma patients.Several different methods have been employed to evaluate bronchial wall thickening, including manual or computer-based detection of bronchi,<a class="elsevierStyleCrossRef" href="#bib0265">53</a> evaluation of different amounts of bronchi<a class="elsevierStyleCrossRef" href="#bib0270">54</a> or, even, three-dimensional evaluation of lung structure.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> All these methods have been proved as valid, to assess airway remodelling<a class="elsevierStyleCrossRefs" href="#bib0280">56,57</a> and have been compared with histological techniques.<a class="elsevierStyleCrossRef" href="#bib0290">58</a> Finally, HRCT has been employed to evaluate the relationship between inflammation and airway remodelling<a class="elsevierStyleCrossRef" href="#bib0295">59</a> and to assess the presence of remodelling in asthmatic children<a class="elsevierStyleCrossRef" href="#bib0270">54</a> with encouraging results.Endobronchial ultrasonographyEndobronchial ultrasonography (EBUS) was described in the early 1990s by Hurter et al.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> Its first use was to evaluate the infiltration of different tumours in bronchial wall, and the presence of lymph node infiltration. EBUS is based in ultrasound technique; a probe surrounded by a saline-filled balloon is introduced in bronchi through a bronchoscope. Ultrasounds have sufficient penetration to evaluate the whole bronchial wall (about 2cm) and provide the optimum resolution image.<a class="elsevierStyleCrossRefs" href="#bib0305">61,62</a>EBUS has been demonstrated to be able to distinguish three to five layers of the bronchial wall<a class="elsevierStyleCrossRef" href="#bib0310">62</a> and was first employed to assess bronchial wall thickness by Shaw et al. in 2004.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> Recent studies, like that published by Soja et al.,<a class="elsevierStyleCrossRef" href="#bib0320">64</a> demonstrated the utility of EBUS to measure bronchial wall layers in asthmatic patients, showing no discrepancies with results obtained by HRCT, and the usefulness of the measure of wall area and wall area/total diameter ratio. Published studies have demonstrated neither alterations of bronchial diameter nor wall thickness<a class="elsevierStyleCrossRef" href="#bib0315">63</a> related to ultrasound probe bronchial introduction.According to all these reasons and the absence of radiation, EBUS could play an important role in the diagnosis of airway remodelling in asthma patients.Lung function measurementsDiagnostic tools described previously demonstrated the presence of structural alterations in asthmatic airway. But these structural modifications are accompanied by clinical alterations, responsible for clinical worsening and symptoms. Lung function measurements, combined with structural alteration diagnostic techniques, make it possible to evaluate the asthmatic process in depth. Alterations in lung function tests and airway hyperresponsiveness are the most used tools to evaluate lung modifications among asthmatic patients.Lung function testsFollow-up studies have demonstrated the decline of lung function assessed by bronchial function test, and mainly expressed as forced expiratory volume in 1s (FEV1), in asthmatic patients.<a class="elsevierStyleCrossRef" href="#bib0325">65</a> Lung function decline has been proposed to be related with the presence of remodelling, based on the increment of lung function after corticosteroid treatment in asthma patients.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> According to these theories, bronchial function test has been proposed to be an important tool to explore airway remodelling in asthma. Different studies<a class="elsevierStyleCrossRefs" href="#bib0335">67–69</a> have suggested that decline of lung function (or even AHR as is next described) is related with airway remodelling, expressed as reticular basement membrane thickening.Airway hyperresponsiveness measurementsThe link between airway hyperresponsiveness (AHR) and remodelling is not well defined, and several studies regarding this theory have been published. Results obtained from different authors seem to be contradictory. Whereas the first studies published suggested the existence of a relationship between AHR and an increment in airway remodelling, recent studies suggest that this relationship is not clear. AHR measurement is performed by the inhalation at tidal volume of a bronchoconstrictor agent (methacholine, histamine, manitol, etc.), using a continuous pressurised nebuliser, at different concentrations. Concentration of the bronchoconstrictor agent causing 20% or 15% fall, depending on the agent, in FEV1, named PC20 or PC15, is employed to express test results. Presence of AHR is considered when PC20 is lower than a previously established value for each agent.<a class="elsevierStyleCrossRef" href="#bib0350">70</a>Morphometric in vitro models, such as that proposed by Heather L. Gillis et al.<a class="elsevierStyleCrossRef" href="#bib0355">71</a> in 1999, demonstrated a connection between airway remodelling, airway smooth muscle and airway hyperresponsiveness (AHR). Laprise et al.<a class="elsevierStyleCrossRef" href="#bib0360">72</a> also reached the same conclusion in a follow-up study that included subjects with AHR but without asthma symptoms; some patients developed asthma symptoms and all of them presented an increment of remodelling markers and subepithelial fibrosis in bronchial biopsies. A study developed by Kariyawasam et al.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> including 30 atopic patients with asthma symptoms and AHR defined as methacholine PC20 of 8mg/ml or less, or a FEV1 increment higher than 15% to β2-agonist, supported these results. Allergen challenge test was performed and airway remodelling was assessed by bronchoscopy with bronchial biopsies at baseline, 24h and seven days after challenge test. Inflammation-related mediators were also evaluated. Results showed that remodelling-related mediators persisted elevated seven days, whereas inflammation related mediators decreased in the first 24h after challenge tests. These results suggest that remodelling is related with AHR increment after exposition to allergen in asthmatic patients.On the other hand, studies like that performed by Siddiqui et al.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> in 2008 including asthmatic and non-asthmatic eosinophilic bronchitis (EB) patients showed no relation between AHR and airway remodelling. There were no differences in remodelling structural changes (defined as an increment in ASM or reticular basement membrane thickening) assessed by bronchial biopsy, between asthmatic patients (that presented AHR) and EB patients (without AHR), although both groups of patients showed differences when compared with a healthy control group.The relationship between AHR and airway remodelling could play an important role when evaluating the presence of structural alterations in the airway. But discrepancies between studies make new studies to assess this relationship necessary.ConclusionsAsthma airway remodelling has become an important way of evaluating asthma severity, asthmatic response to treatment and lung function decline. Since its description as an asthma characteristic, airway remodelling has been evaluated in many different ways, including invasive and non-invasive techniques.Invasive techniques bring us information about bronchial structural alterations, obtaining this information directly from pathological tissue. Invasive techniques permit us to measure histological modification placed in bronchi layers, as well as inflammatory and fibrotic cell infiltration. Invasive methods were the first tools that made airway remodelling measurement possible, and play, undoubtedly, a remarkable role in its evaluation. Unfortunately, invasive methods (principally BB and BAL) present some disadvantages such as the need for specially trained personal and hospital environment, risks for patients and elevated costs.Non-invasive techniques were developed to reduce the disadvantages of invasive methods. Non-invasive techniques measure airway remodelling-related markers, such as cytokines, inflammatory mediators and others. These methods are based on the evaluation of exhaled breath (FeNO and EBC), sputum (IS), lung function (pulmonary function test and AHR measurement) or lung images (CT and EBUS). The risk associated to invasive techniques has been avoided, and in most of these non-invasive methods, no trained personal is needed and they should not be performed in a hospital environment. For example, FeNO is an inexpensive technique that could be carried out in an outpatient clinic and without risks for the patient. But unfortunately, non-invasive techniques present other disadvantages like radiation exposition and elevated cost (referring to HRCT), the need for expensive laboratory equipment (especially in IS and EBC technique) and, sometimes, they are not free of risks for the patients (i.e. EBUS).In conclusion, methods assessing airway remodelling in asthma have been greatly improved in the last years, making them more secure, reliable and generalised than before. Nevertheless, the relevance of these techniques still remains unclear and further studies are necessary to elucidate if it is of worth to perform some of them in routine clinic.FundingAuthors do not report any funding for this article.Conflict of interestThe authors declare not to have any conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres86099" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec74263" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Remodelling physiopathology" ] 4 => array:3 [ "identificador" => "sec0015" "titulo" => "Invasive methods" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Bronchial biopsies" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Bronchoalveolar lavage" ] ] ] 5 => array:3 [ "identificador" => "sec0030" "titulo" => "Non-invasive methods" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Induced sputum" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Exhaled nitric oxide" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Exhaled breath condensate" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Peripheral blood, urine, saliva and other biological fluids" ] ] ] 6 => array:3 [ "identificador" => "sec0055" "titulo" => "Imaging techniques" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "High resolution computerised tomography" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Endobronchial ultrasonography" ] ] ] 7 => array:3 [ "identificador" => "sec0070" "titulo" => "Lung function measurements" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Lung function tests" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Airway hyperresponsiveness measurements" ] ] ] 8 => array:2 [ "identificador" => "sec0085" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0090" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-10-14" "fechaAceptado" => "2011-11-11" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec74263" "palabras" => array:7 [ 0 => "Airway remodelling" 1 => "Asthma" 2 => "Diagnosis" 3 => "Imaging techniques" 4 => "Invasive methods" 5 => "Lung function measurements" 6 => "Non-invasive methods" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Asthma is an inflammatory disease of the lower airways characterised by the presence of airway inflammation, reversible airflow obstruction and airway hyperresponsiveness and alterations on the normal structure of the airways, known as remodelling. Remodelling is characterised by the presence of metaplasia of mucous glands, thickening of the lamina reticularis, increased angiogenesis, subepithelial fibrosis and smooth muscle hypertrophy/hyperplasia. Several techniques are being optimised at present to achieve a suitable diagnosis for remodelling.Diagnostic tools could be divided into two groups, namely invasive and non-invasive methods. Invasive techniques bring us information about bronchial structural alterations, obtaining this information directly from pathological tissue, and permit measure histological modification placed in bronchi layers as well as inflammatory and fibrotic cell infiltration. Non-invasive techniques were developed to reduce invasive methods disadvantages and measure airway remodelling-related markers such as cytokines, inflammatory mediators and others.An exhaustive review of diagnostic tools used to analyse airway remodelling in asthma, including the most useful and usually employed methods, as well as the principal advantages and disadvantages of each of them, bring us concrete and summarised information about all techniques used to evaluate alterations on the structure of the airways. A deep knowledge of these diagnostic tools will make an early diagnosis of airway remodelling possible and, probably, early diagnosis will play an important role in the near future of asthma." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Invasive methods \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronchial biopsies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronchoalveolar lavage (BAL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-invasive methods \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induced sputum \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exhaled nitric oxide \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Exhaled breath condensate \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biological fluids \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Imaging techniques \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High resolution computerised tomography (HRCT) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Endobronchial ultrasonography \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lung function measurements \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lung function tests \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Airway hyperresponsiveness measurements \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab165458.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic tools employed to assess airway remodelling." ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Cell types \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mediators/proteins produced \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eosinophil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inflammation, growth factor production (TGFβ) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGFβ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cell \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mediators production (histamine, tryptase, growth factors) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histamine, tryptase, VEGF \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mediators production when injured \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGFβ, EGF, VEGF, PGE2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Th2 cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Subepithelial fibrosis and smooth muscle hyperplasia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-5, IL-13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regulatory t cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Down-regulate Th2 cells function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-10, TGFβ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myofibroblast \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bronchial contraction, ECM secretion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tenascin C, fibronectine, collagens I, III and V \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab165459.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Most relevant cells involved in bronchial remodelling." ] ] 2 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "MMP-9 (matrix metalloproteinase-9)." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Mediators \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Producing cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Function \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TGFβ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eosinophils, regulatory T cells, epithelial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fibrosis, smooth muscle proliferation, mucus production \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EGF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial cells migration \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">VEGF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cells, epithelial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular remodelling, mucus metaplasia, smooth muscle proliferation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Th2 cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myofibroblasts activation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Th2 cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Fibrosis, mucus production \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TNFα \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cells, macrophages \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smooth muscle proliferation, inflammatory cells activation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MMP-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Degradation of extracellular matrix \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Histamine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cells, basophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Vascular permeability increment \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tryptase \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cells, basophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Smooth muscle proliferation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PGE2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epithelial cells, smooth muscle cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Down-regulate smooth muscle and myofibroblasts proliferation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 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Adachi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2002" "volumen" => "122" "paginaInicial" => "1622" "paginaFinal" => "1626" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12426262" "web" => "Medline" ] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relationship between airway basement membrane thickness and lung function tests in patients with asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Kościuch" 1 => "T. Przybyłowski" 2 => "K. Górska" 3 => "R. Krenke" 4 => "W. Baran" 5 => "M. Kujawa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Pneumonol Alergol Pol" "fecha" => "2009" "volumen" => "77" "paginaInicial" => "256" "paginaFinal" => "263" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19591096" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0015028205033376" "estado" => "S300" "issn" => "00150282" ] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparision of bronchial hyperresponsiveness to methacholine and adenosine and airway inflammation markers in patients with suspected asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "L. Manso" 1 => "M.F. Madero" 2 => "M. Ruiz-García" 3 => "M. Fernández-Nieto" …1 ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.3109/02770903.2011.565850" "Revista" => array:6 [ "tituloSerie" => "J Asthma" "fecha" => "2011" "volumen" => "48" "paginaInicial" => "335" "paginaFinal" => "340" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Airway remodeling in asthma amplifies heterogeneities in smooth muscle shortening causing hyperresponsiveness" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Appl Physiol" "fecha" => "1999" "volumen" => "86" "paginaInicial" => "2001" "paginaFinal" => "2012" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Asymptomatic airway hyperresponsiveness: relationships with airway inflammation and remodelling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "1999" "volumen" => "14" "paginaInicial" => "63" "paginaFinal" => "73" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 72 => array:3 [ "identificador" => "bib0365" "etiqueta" => "73" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Remodeling and airway hyperresponsiveness but not cellular inflammation persist after allergen challenge in asthma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.200609-1260OC" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2007" "volumen" => "175" "paginaInicial" => "896" "paginaFinal" => "904" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 73 => array:3 [ "identificador" => "bib0370" "etiqueta" => "74" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Airway hyperresponsiveness is dissociated from airway wall structural remodeling" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.jaci.2008.05.020" "Revista" => array:6 [ "tituloSerie" => "J Allergy Clin Immunol" "fecha" => "2008" "volumen" => "122" "paginaInicial" => "335" "paginaFinal" => "341" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/03010546/0000004000000002/v1_201304101104/S0301054611003612/v1_201304101104/en/main.assets" "Apartado" => array:4 [ "identificador" => "5555" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Review" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/03010546/0000004000000002/v1_201304101104/S0301054611003612/v1_201304101104/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0301054611003612?idApp=UINPBA00004N"]

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L. Manso

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mansomd@hotmail.com

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, M. Reche, M.A. Padial, T. Valbuena, C. Pascual

Allergy Department, Hospital Infanta Sofía, San Sebastián de los Reyes, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Asthma is an inflammatory disease of lower airways characterised by the presence of airway inflammation&#44; reversible airflow obstruction and airway hyperresponsiveness and&#44; as lately described&#44; alterations on the normal structure of the airways&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The presence of these alterations&#44; known as remodelling&#44; has been postulated to play an important role in the pathogenesis of asthma&#44; and the absence of treatment of these alterations may be a lack in the prognosis of asthma patients&#46; Remodelling is characterised by the presence of metaplasia of mucous glands&#44; thickening of the lamina reticularis&#44; increased angiogenesis&#44; subepithelial fibrosis and smooth muscle hypertrophy&#47;hyperplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Several immune cells have been related with the pathogenesis of airway remodelling&#44; including T cells&#44; eosinophils&#44; mast cells&#44; fibroblasts and other epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> These cells could be evaluated by different invasive methods &#40;including bronchial biopsies&#44; analysis of bronchoalveolar lavage solid phase&#44; etc&#46;&#41; or non-invasive methods &#40;i&#46;e&#46; induced sputum solid phase analysis&#41;&#46; Pathogenesis of airway remodelling is also related with structural alterations of the airway&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> which could be diagnosed by imaging techniques &#40;i&#46;e&#46; high resolution computerised tomography&#41; and invasive methods such as bronchial biopsies&#46; The presence of different pro-inflammatory mediators and cytokines involved in remodelling<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> could be evaluated through invasive methods &#40;e&#46;g&#46; detecting mediators in bronchial biopsies or bronchoalveolar lavage&#41;&#44; as well as indirect methods &#40;including analysis of induced sputum liquid phase&#41;&#46; Finally&#44; asthma has always been related with functional alterations&#44; evaluation of bronchial hyperresponsiveness and lung function test could bring us important information about the level of bronchial remodelling&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Early diagnosis of airway remodelling will play an important role in the near future of asthma&#59; several techniques are being optimised at present to achieve a suitable diagnosis&#46; All these techniques are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Remodelling physiopathology</span><p id="par0020" class="elsevierStylePara elsevierViewall">Remodelling is characterised&#44; as previously described&#44; by the presence of different structural alterations such as metaplasia of mucous glands&#44; thickening of the lamina reticularis&#44; increased angiogenesis&#44; subepithelial fibrosis and smooth muscle hypertrophy&#47;hyperplasia&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> All these structural modifications are caused by different immunological-related mediators or cellular mechanisms&#46; Structural alterations are accompanied by functional changes&#44; and both sorts of changes are obviously related&#46; Regarding these aspects it is essential to introduce the epithelial mesenchymal trophic unit &#40;EMTU&#41; concept&#44; described by Plopper and Evans&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The EMTU is a concept linked to the existence of an attenuated fibroblast layer between epithelial and mesenchymal cells&#46; These fibroblasts are able to differentiate into myofibroblasts&#44; as a response to some local stimuli&#44; and secrete different cellular mediators and proteins known as extracellular matrix &#40;ECM&#41;&#46; ECM is a dynamic structure that influences epithelium cells&#44; smooth muscle cells&#44; blood vessels and neural terminations&#46; Activated EMTU is related with the persistence of airway inflammation&#44; the abnormal reparation of damaged epithelium and fibroblasts proliferation&#44; creating a microenvironment similar to a chronic wound in the asthmatic airway&#46; In short&#44; EMTU is referred to different airway structures&#44; cells layers and secreted mediators that control airway inflammation and repair process&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">It is essential to understand how EMTU controls the different processes involving airway structure&#44; and the important role that ECM plays in airway remodelling&#46; After an acute epithelial injury &#40;i&#46;e&#46; tobacco smoke or allergen exposure&#44; viruses&#41;&#44; an increment in the number of fibroblasts occurs&#44; accompanied by an increase in the ECM production &#40;including proteins like fibronectin&#44; tenascin and I&#8211;III&#8211;V collagen&#41; that alters smooth muscle function&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> All these changes are regulated by several cytokines and pro-fibrotic mediators&#44; such as transforming growth factor &#40;TGF&#41;-&#946; and epidermal growth factor &#40;EGF&#41; mainly&#44; resulting in an increment of subepithelial fibrosis&#46; Simultaneously&#44; increased angiogenesis and vascular permeability promoted by vascular endothelial growth factors &#40;VEGFs&#41; secreted by smooth muscle cells&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> induce airway oedema and inflammatory cells recruitment &#40;mainly eosinophils and mast cells&#41;&#46; All these changes induce smooth muscle and epithelial cell proliferation&#44; with an increased production of different cytokines like interleukin 1 &#40;IL-1&#41;&#44; IL-5&#44; IL-13 or tumour necrosis factor-&#945; &#40;TNF-&#945;&#41;&#44; lipidic mediators like leukotriene D<span class="elsevierStyleInf">4</span> &#40;LTD<span class="elsevierStyleInf">4</span>&#41; or prostaglandine E<span class="elsevierStyleInf">2</span> &#40;PGE<span class="elsevierStyleInf">2</span>&#41; and growth factors like EGF&#44; TGF-&#946;&#44; platelet derived growth factors &#40;PDGFs&#41; or VEGFs &#40;<a class="elsevierStyleCrossRefs" href="#tbl0010">Tables 2 and 3</a>&#41;&#46; Production of all these mediators provides a source of chronic inflammation and fibrosis that causes all the structural alterations mentioned above&#44; leading the asthmatic airway to a remodelling process&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Invasive methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">Several years ago specimens obtained from post-mortem studies brought us the first information about structural alterations in asthmatic lungs&#46; Invasive methods of analysing bronchial morphology are able to quantify remodelling alterations in a direct way&#44; showing structural modifications and bronchial wall cell infiltration present in bronchial specimens&#46; These methods allow evaluating inflammatory and epithelial cells&#44; as well as cytokines&#44; inflammatory and pro-fibrotic mediators that are present in subjects in different moments of their process&#46; Invasive methods are usually employed in investigational studies and have been used to evaluate evolution of asthma and response to treatment&#46; The most commonly employed invasive methods&#44; including bronchial biopsies and bronchoalveolar lavage&#44; will be described below&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bronchial biopsies</span><p id="par0035" class="elsevierStylePara elsevierViewall">Bronchial biopsy &#40;BB&#41; was first employed to evaluate asthma severity in the early 1960s&#44; but it was in the 1990s when BB became extensively used to assess airway remodelling in asthmatic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> BB allows evaluating structural and morphological changes in bronchial specimens with the lack of analysing not the entire airway wall&#44; but superficial airway layers&#46; At least&#44; five to eight specimens should be obtained for a correct diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Two different methods for obtaining BB have been usually employed&#58; endobronchial biopsy &#40;EBB&#41; and transbronchial biopsy &#40;TBB&#41;&#46; Both techniques should be performed by specialists in a hospital environment using flexible bronchoscopy&#46; EBB makes it possible to obtain large airway specimens&#44; while TBB permits to obtain distal airway and alveolar tissue specimens&#46; EBB presents fewer complications than TBB&#44; but information regarding airway remodelling is more extensive when TBB is employed&#44; this is due to the capability of analysing distal airway remodelling&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Both biopsy techniques have been shown to give similar results when compared with surgically obtained specimens&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">BB has been employed in several studies to assess airway remodelling&#44; some of them employing EBB<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#8211;14</span></a> and another TBB&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and some studies have even employed and compared both techniques&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> Most of these studies have analysed the presence of inflammatory cells&#44; fibroblasts and inflammatory mediators in bronchial specimens&#44; but BB has also been employed to elucidate asthmatic patients&#8217; response to corticosteroid treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;20</span></a> BB obtained before and after corticosteroid treatment gives important information about the airway structural modifications produced by these drugs&#46; The use of BB has been implemented in the past years&#44; regarding different aspects of asthma pathogenesis&#44; and BB has been employed&#44; for example&#44; to evaluate the relationship between airway remodelling and airway hyperresponsiveness<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> or between airway remodelling and inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In short&#44; BB has probably become the most useful technique to evaluate airway remodelling and its relationship with other aspects of asthma pathology&#44; such as airway inflammation or treatment response&#46; Even though BB is undoubtedly useful&#44; it also presents some disadvantages such as the risk of severe complications &#40;like bleeding or pneumothorax&#41;&#59; the difficulty to obtain suitable specimens&#59; or the requirement of trained personal to perform flexible bronchoscopy&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Bronchoalveolar lavage</span><p id="par0050" class="elsevierStylePara elsevierViewall">Bronchoalveolar lavage &#40;BAL&#41; could be considered a complementary tool of bronchial biopsies&#44; since both kinds of samples should be obtained by bronchoscopy techniques&#46; BAL could be obtained in the same intervention as bronchial biopsies&#44; and could give us important information about cells and airway remodelling-related markers&#44; without biopsy-associated risks&#46; The BAL technique consists in instilling saline solution&#44; through the instrumentation channel of a bronchoscope&#44; into a segmental or subsegmental bronchus&#46; After saline instilling&#44; this solution is then aspirated into a sterile container&#46; Specimens obtained should be processed and centrifuged to obtain a solid and a liquid phase&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">As well as biopsy&#44; BAL makes it possible to evaluate inflammatory cells related to airway remodelling in BAL solid phase obtained after centrifugation&#46; Different articles<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;25</span></a> have shown elevated levels of T regulatory cells&#44; fibrocytes and neutrophils in BAL from asthmatic subjects&#44; and its relationship with airway inflammation and remodelling&#46; But&#44; BAL has also been employed to analyse remodelling-related markers&#44; for these studies the liquid phase of BAL was obtained after centrifugation&#46; Different markers&#44; such as transforming growth factor-&#946;1 &#40;TGF-&#946;1&#41; or insulin-like growth factor binding protein-3 &#40;IGFBP3&#41; presented modified levels in the liquid phase of BAL&#44; when compared with control subjects&#8217; ones&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In resume&#44; BAL presents advantages like the possibility of obtaining samples simultaneously to bronchial biopsies&#44; evaluating inflammatory cells or remodelling-related mediators&#44; and evaluation simplicity&#46; On the other hand&#44; BAL disadvantages lies in the difficulty to obtain samples &#40;bronchoscopy is required&#41; and the limited amount of epithelium and epithelial underlying layers cells obtained&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Non-invasive methods</span><p id="par0065" class="elsevierStylePara elsevierViewall">In the last 50 years clinical practice has tried to reduce the use of invasive techniques for diagnosing airway pathologies&#46; Technical and clinical difficulties involving direct or invasive methods have promoted the development of different non-invasive methods to evaluate the presence of airway remodelling in asthmatic patients&#46; Non-invasive methods are based in the study of different inflammatory cells and mediators related with airway remodelling obtained from sputum&#44; bronchoalveolar lavage and other systemic fluids&#44; or from breath exhaled&#46; Non-invasive methods bring information about clinical features as well as investigational data of evolution and modification of asthmatic disease&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Induced sputum</span><p id="par0070" class="elsevierStylePara elsevierViewall">Induced sputum &#40;IS&#41; first protocol was described by Bickerman in 1958<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#59; after this description&#44; several studies have demonstrated the usefulness of IS when diagnosing different respiratory diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Sputum induction consists in the inhalation of increasing concentrations of hypertonic saline &#40;3&#37;&#44; 4&#37; and 5&#37;&#41; during 10<span class="elsevierStyleHsp" style=""></span>min&#44; and obtaining the sputum produced in a sterile container&#46; Solid sputum material is separated from saliva&#44; treated with 0&#46;1&#37; dithiothreitol &#40;DTT&#41; and mucus is removed by filtration&#46; Material obtained is centrifuged to separate liquid and solid phase&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> IS analysis&#44; after processing and centrifugation of samples&#44; permits to evaluate levels of inflammatory cells&#44; lipidic mediators and cytokines in a safe way&#44; even in moderate or severe asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Flow cytometry or cytospin analysis and microscopical cell count&#44; performed in solid phase of IS&#44; make it possible for investigators to establish a cellular pattern involving respiratory pathologies&#44; including asthma airway remodelling&#46; For example&#44; Kaminska et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> tried to identify the inflammatory cell patterns of airway remodelling in different subtypes of severe asthma&#59; eosinophils count performed in IS showed to not be able to identify such different subtypes&#46; Eosinophils count in IS&#44; together with exhaled nitric oxide and remodelling-related markers like interleukins&#44; has also been employed in children to identify two different phenotypes of moderate asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Recently&#44; Broekema et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> employed IS to evaluate differences in airway remodelling between actually asthmatic patients and patients with clinical or complete asthma remission&#46; Finally&#44; IS solid phase has also been demonstrated to be useful when evaluating airway remodelling response to corticosteroid treatment in asthmatic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The liquid phase of IS has been employed to evaluate levels of pro-inflammatory markers and cytokines involving airway remodelling&#46; This is probably the most known featuring of IS&#44; and it has been defined as a relevant technique when evaluating different remodelling markers such as TGF-&#946;1&#44; vascular endothelial growth factor &#40;VEGF&#41;&#44; matrix metalloproteinase-9 &#40;MMP-9&#41; and others&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#8211;38</span></a> But analysis of the liquid phase of IS&#44; has also been demonstrated as a useful tool to evaluate airway remodelling differences between different coughing pathologies&#44; like asthma and eosinophilic bronchitis&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In summary&#44; due to its different applications&#59; the fact that it is easy to obtain&#59; and the absence of risk for patients&#44; IS has become&#44; probably&#44; the most useful technique to evaluate airway remodelling in a non-invasive manner&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Exhaled nitric oxide</span><p id="par0090" class="elsevierStylePara elsevierViewall">Exhaled nitric oxide &#40;FeNO&#41; has been related with the presence of inflammation in bronchi of asthmatic patients&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> and it has been also proposed as an efficient technique to evaluate asthmatic exacerbations<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> and asthmatic response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> The method of FeNO measuring is simple and is performed by breathing through a chemiluminescence analyser for about 6<span class="elsevierStyleHsp" style=""></span>s&#44; according to the American Thoracic Society &#40;ATS&#41; and European Respiratory Society &#40;ERS&#41; guidelines&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Several studies have suggested that FeNO could represent an easy and accessible tool to assess airway remodelling in adults as well as in children suffering asthma&#46; Ketai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> demonstrated that FeNO levels were elevated during acute asthma exacerbations&#44; related with bronchial wall area assessed by high-resolution computed tomography&#44; but these elevated levels did not persist when acute exacerbations were treated&#46; When the FeNO and airway remodelling relationship has been measured in children<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> a positive correlation with FeNO has been demonstrated&#46; This correlation has also been shown when adolescents were evaluated&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> and elevated levels of FeNO were related with AHR and airway remodelling in children &#8805;12 years of age&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Although FeNO is well related with bronchial inflammation and seems to be linked to airway remodelling&#44; this last relationship still remains unclear&#46; Most studies that have been performed evaluating FeNO levels present a lack of dispersion referring to age of patients&#44; severity of asthma and methods used to evaluate remodelling&#46; More specific studies&#44; especially regarding severity of asthma&#44; are necessary to assure that FeNO is a useful tool to evaluate airway remodelling&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Exhaled breath condensate</span><p id="par0105" class="elsevierStylePara elsevierViewall">Not many articles regarding the use of exhaled breath condensate &#40;EBC&#41; in the study of airway remodelling have been published&#46; Despite the recent use of EBC to establish the existence of airway remodelling in asthmatic patients&#44; it seems to be a useful tool&#46; To obtain EBC&#44; a refrigerating exhaled breath circuit should be used&#46; Patients have to breathe through this circuit at tidal volume for 10<span class="elsevierStyleHsp" style=""></span>min and samples obtained should be processed before analysing&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Lex et al&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> demonstrated the relationship between levels of cystenyl leukotrienes &#40;cysLTs&#41;&#44; previously described as a marker for airway remodelling&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> measured in EBC&#44; and airway remodelling&#44; assessed as reticular basement membrane thickening in biopsies obtained in children&#46; Another study has described the relationship between Endotelin-1 &#40;ET-1&#41;&#44; another marker implicated in airway remodelling&#44; measured in EBC&#44; with different degrees of asthma severity in adult asthmatic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Evaluation of EBC levels of remodelling-related markers has been demonstrated as a valid technique when evaluating remodelling&#44; although more studies are necessary to assure this point&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Peripheral blood&#44; urine&#44; saliva and other biological fluids</span><p id="par0120" class="elsevierStylePara elsevierViewall">The analysis of airway remodelling-related mediators in different peripheral fluids seems to be an economical and easy way to evaluate airway remodelling levels in asthmatic patients&#46; Peripheral fluids have been employed in murine models to evaluate these remodelling markers and&#44; in the past years&#44; have been developed in humans&#46; MMP-9 levels in asthmatic patients&#8217; blood have been evaluated in different studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> showing contradictory results&#46; Recently&#44; another study performed in humans&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> has evaluated levels of Fibulin-1 &#40;a secreted glycoprotein that assists in stabilising extracellular matrix&#41; in serum of asthmatic patients and healthy volunteers&#59; Fibulin-1 levels were significantly increased in asthmatic patients&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Further studies are necessary&#44; involving different peripheral fluids&#44; cells and related markers&#44; to establish the relevance of these techniques when evaluating airway remodelling&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Imaging techniques</span><p id="par0130" class="elsevierStylePara elsevierViewall">Recent advances in imaging techniques provide asthma with a new course to evaluate the presence of remodelling in bronchial airway&#46; Improvement in computerised tomography &#40;CT&#41; resolution&#44; the employing of new collimation techniques and new reconstruction algorithms bring imaging techniques a leading role in asthma evaluation&#46; Moreover&#44; improvements in endoscopic ultrasonography techniques&#44; including smaller probes and better resolution images&#44; complete the advances that make the indirect evaluation of airway remodelling through imaging techniques possible&#46;</p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">High resolution computerised tomography</span><p id="par0135" class="elsevierStylePara elsevierViewall">Bronchial wall thickening has been described as one of the most important findings in asthma patients but not in healthy subjects&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> but its evaluation required obtaining bronchial biopsies&#46; To solve the lack of obtaining bronchial specimens&#44; computerised tomography &#40;CT&#41; and especially high resolution CT &#40;HRCT&#41; have been employed in several trials as a bloodless method to evaluate bronchial airway structural changes&#46; In contrast&#44; HRCT presents high radiation exposition and an elevated cost as principal objections to its extended use&#46; Due to these disadvantages&#44; at present the CT technique is limited to investigational trials and severe asthma patients&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Several different methods have been employed to evaluate bronchial wall thickening&#44; including manual or computer-based detection of bronchi&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> evaluation of different amounts of bronchi<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> or&#44; even&#44; three-dimensional evaluation of lung structure&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> All these methods have been proved as valid&#44; to assess airway remodelling<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;57</span></a> and have been compared with histological techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Finally&#44; HRCT has been employed to evaluate the relationship between inflammation and airway remodelling<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> and to assess the presence of remodelling in asthmatic children<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> with encouraging results&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Endobronchial ultrasonography</span><p id="par0145" class="elsevierStylePara elsevierViewall">Endobronchial ultrasonography &#40;EBUS&#41; was described in the early 1990s by Hurter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Its first use was to evaluate the infiltration of different tumours in bronchial wall&#44; and the presence of lymph node infiltration&#46; EBUS is based in ultrasound technique&#59; a probe surrounded by a saline-filled balloon is introduced in bronchi through a bronchoscope&#46; Ultrasounds have sufficient penetration to evaluate the whole bronchial wall &#40;about 2<span class="elsevierStyleHsp" style=""></span>cm&#41; and provide the optimum resolution image&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">61&#44;62</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">EBUS has been demonstrated to be able to distinguish three to five layers of the bronchial wall<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> and was first employed to assess bronchial wall thickness by Shaw et al&#46; in 2004&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> Recent studies&#44; like that published by Soja et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> demonstrated the utility of EBUS to measure bronchial wall layers in asthmatic patients&#44; showing no discrepancies with results obtained by HRCT&#44; and the usefulness of the measure of wall area and wall area&#47;total diameter ratio&#46; Published studies have demonstrated neither alterations of bronchial diameter nor wall thickness<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> related to ultrasound probe bronchial introduction&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">According to all these reasons and the absence of radiation&#44; EBUS could play an important role in the diagnosis of airway remodelling in asthma patients&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Lung function measurements</span><p id="par0160" class="elsevierStylePara elsevierViewall">Diagnostic tools described previously demonstrated the presence of structural alterations in asthmatic airway&#46; But these structural modifications are accompanied by clinical alterations&#44; responsible for clinical worsening and symptoms&#46; Lung function measurements&#44; combined with structural alteration diagnostic techniques&#44; make it possible to evaluate the asthmatic process in depth&#46; Alterations in lung function tests and airway hyperresponsiveness are the most used tools to evaluate lung modifications among asthmatic patients&#46;</p><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Lung function tests</span><p id="par0165" class="elsevierStylePara elsevierViewall">Follow-up studies have demonstrated the decline of lung function assessed by bronchial function test&#44; and mainly expressed as forced expiratory volume in 1<span class="elsevierStyleHsp" style=""></span>s &#40;FEV1&#41;&#44; in asthmatic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> Lung function decline has been proposed to be related with the presence of remodelling&#44; based on the increment of lung function after corticosteroid treatment in asthma patients&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a> According to these theories&#44; bronchial function test has been proposed to be an important tool to explore airway remodelling in asthma&#46; Different studies<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">67&#8211;69</span></a> have suggested that decline of lung function &#40;or even AHR as is next described&#41; is related with airway remodelling&#44; expressed as reticular basement membrane thickening&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Airway hyperresponsiveness measurements</span><p id="par0170" class="elsevierStylePara elsevierViewall">The link between airway hyperresponsiveness &#40;AHR&#41; and remodelling is not well defined&#44; and several studies regarding this theory have been published&#46; Results obtained from different authors seem to be contradictory&#46; Whereas the first studies published suggested the existence of a relationship between AHR and an increment in airway remodelling&#44; recent studies suggest that this relationship is not clear&#46; AHR measurement is performed by the inhalation at tidal volume of a bronchoconstrictor agent &#40;methacholine&#44; histamine&#44; manitol&#44; etc&#46;&#41;&#44; using a continuous pressurised nebuliser&#44; at different concentrations&#46; Concentration of the bronchoconstrictor agent causing 20&#37; or 15&#37; fall&#44; depending on the agent&#44; in FEV1&#44; named PC<span class="elsevierStyleInf">20</span> or PC<span class="elsevierStyleInf">15</span>&#44; is employed to express test results&#46; Presence of AHR is considered when PC<span class="elsevierStyleInf">20</span> is lower than a previously established value for each agent&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Morphometric in vitro models&#44; such as that proposed by Heather L&#46; Gillis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> in 1999&#44; demonstrated a connection between airway remodelling&#44; airway smooth muscle and airway hyperresponsiveness &#40;AHR&#41;&#46; Laprise et al&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a> also reached the same conclusion in a follow-up study that included subjects with AHR but without asthma symptoms&#59; some patients developed asthma symptoms and all of them presented an increment of remodelling markers and subepithelial fibrosis in bronchial biopsies&#46; A study developed by Kariyawasam et al&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> including 30 atopic patients with asthma symptoms and AHR defined as methacholine PC<span class="elsevierStyleInf">20</span> of 8<span class="elsevierStyleHsp" style=""></span>mg&#47;ml or less&#44; or a FEV1 increment higher than 15&#37; to &#946;<span class="elsevierStyleInf">2</span>-agonist&#44; supported these results&#46; Allergen challenge test was performed and airway remodelling was assessed by bronchoscopy with bronchial biopsies at baseline&#44; 24<span class="elsevierStyleHsp" style=""></span>h and seven days after challenge test&#46; Inflammation-related mediators were also evaluated&#46; Results showed that remodelling-related mediators persisted elevated seven days&#44; whereas inflammation related mediators decreased in the first 24<span class="elsevierStyleHsp" style=""></span>h after challenge tests&#46; These results suggest that remodelling is related with AHR increment after exposition to allergen in asthmatic patients&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">On the other hand&#44; studies like that performed by Siddiqui et al&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> in 2008 including asthmatic and non-asthmatic eosinophilic bronchitis &#40;EB&#41; patients showed no relation between AHR and airway remodelling&#46; There were no differences in remodelling structural changes &#40;defined as an increment in ASM or reticular basement membrane thickening&#41; assessed by bronchial biopsy&#44; between asthmatic patients &#40;that presented AHR&#41; and EB patients &#40;without AHR&#41;&#44; although both groups of patients showed differences when compared with a healthy control group&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">The relationship between AHR and airway remodelling could play an important role when evaluating the presence of structural alterations in the airway&#46; But discrepancies between studies make new studies to assess this relationship necessary&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0190" class="elsevierStylePara elsevierViewall">Asthma airway remodelling has become an important way of evaluating asthma severity&#44; asthmatic response to treatment and lung function decline&#46; Since its description as an asthma characteristic&#44; airway remodelling has been evaluated in many different ways&#44; including invasive and non-invasive techniques&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Invasive techniques bring us information about bronchial structural alterations&#44; obtaining this information directly from pathological tissue&#46; Invasive techniques permit us to measure histological modification placed in bronchi layers&#44; as well as inflammatory and fibrotic cell infiltration&#46; Invasive methods were the first tools that made airway remodelling measurement possible&#44; and play&#44; undoubtedly&#44; a remarkable role in its evaluation&#46; Unfortunately&#44; invasive methods &#40;principally BB and BAL&#41; present some disadvantages such as the need for specially trained personal and hospital environment&#44; risks for patients and elevated costs&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Non-invasive techniques were developed to reduce the disadvantages of invasive methods&#46; Non-invasive techniques measure airway remodelling-related markers&#44; such as cytokines&#44; inflammatory mediators and others&#46; These methods are based on the evaluation of exhaled breath &#40;FeNO and EBC&#41;&#44; sputum &#40;IS&#41;&#44; lung function &#40;pulmonary function test and AHR measurement&#41; or lung images &#40;CT and EBUS&#41;&#46; The risk associated to invasive techniques has been avoided&#44; and in most of these non-invasive methods&#44; no trained personal is needed and they should not be performed in a hospital environment&#46; For example&#44; FeNO is an inexpensive technique that could be carried out in an outpatient clinic and without risks for the patient&#46; But unfortunately&#44; non-invasive techniques present other disadvantages like radiation exposition and elevated cost &#40;referring to HRCT&#41;&#44; the need for expensive laboratory equipment &#40;especially in IS and EBC technique&#41; and&#44; sometimes&#44; they are not free of risks for the patients &#40;i&#46;e&#46; EBUS&#41;&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">In conclusion&#44; methods assessing airway remodelling in asthma have been greatly improved in the last years&#44; making them more secure&#44; reliable and generalised than before&#46; Nevertheless&#44; the relevance of these techniques still remains unclear and further studies are necessary to elucidate if it is of worth to perform some of them in routine clinic&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Funding</span><p id="par0210" class="elsevierStylePara elsevierViewall">Authors do not report any funding for this article&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0215" class="elsevierStylePara elsevierViewall">The authors declare not to have any conflict of interest&#46;</p></span></span>"
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          "identificador" => "xres86099"
          "titulo" => "Abstract"
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        1 => array:2 [
          "identificador" => "xpalclavsec74263"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        3 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Remodelling physiopathology"
        ]
        4 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Invasive methods"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Bronchial biopsies"
            ]
            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Bronchoalveolar lavage"
            ]
          ]
        ]
        5 => array:3 [
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          "titulo" => "Non-invasive methods"
          "secciones" => array:4 [
            0 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Induced sputum"
            ]
            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Exhaled nitric oxide"
            ]
            2 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Exhaled breath condensate"
            ]
            3 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Peripheral blood&#44; urine&#44; saliva and other biological fluids"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0055"
          "titulo" => "Imaging techniques"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "High resolution computerised tomography"
            ]
            1 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Endobronchial ultrasonography"
            ]
          ]
        ]
        7 => array:3 [
          "identificador" => "sec0070"
          "titulo" => "Lung function measurements"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0075"
              "titulo" => "Lung function tests"
            ]
            1 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Airway hyperresponsiveness measurements"
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Conclusions"
        ]
        9 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Funding"
        ]
        10 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Conflict of interest"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2011-10-14"
    "fechaAceptado" => "2011-11-11"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec74263"
          "palabras" => array:7 [
            0 => "Airway remodelling"
            1 => "Asthma"
            2 => "Diagnosis"
            3 => "Imaging techniques"
            4 => "Invasive methods"
            5 => "Lung function measurements"
            6 => "Non-invasive methods"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Asthma is an inflammatory disease of the lower airways characterised by the presence of airway inflammation&#44; reversible airflow obstruction and airway hyperresponsiveness and alterations on the normal structure of the airways&#44; known as remodelling&#46; Remodelling is characterised by the presence of metaplasia of mucous glands&#44; thickening of the lamina reticularis&#44; increased angiogenesis&#44; subepithelial fibrosis and smooth muscle hypertrophy&#47;hyperplasia&#46; Several techniques are being optimised at present to achieve a suitable diagnosis for remodelling&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Diagnostic tools could be divided into two groups&#44; namely invasive and non-invasive methods&#46; Invasive techniques bring us information about bronchial structural alterations&#44; obtaining this information directly from pathological tissue&#44; and permit measure histological modification placed in bronchi layers as well as inflammatory and fibrotic cell infiltration&#46; Non-invasive techniques were developed to reduce invasive methods disadvantages and measure airway remodelling-related markers such as cytokines&#44; inflammatory mediators and others&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">An exhaustive review of diagnostic tools used to analyse airway remodelling in asthma&#44; including the most useful and usually employed methods&#44; as well as the principal advantages and disadvantages of each of them&#44; bring us concrete and summarised information about all techniques used to evaluate alterations on the structure of the airways&#46; A deep knowledge of these diagnostic tools will make an early diagnosis of airway remodelling possible and&#44; probably&#44; early diagnosis will play an important role in the near future of asthma&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Invasive methods</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bronchial biopsies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Bronchoalveolar lavage &#40;BAL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Non-invasive methods</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Induced sputum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Exhaled nitric oxide&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Exhaled breath condensate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Biological fluids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Imaging techniques</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>High resolution computerised tomography &#40;HRCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Endobronchial ultrasonography&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Lung function measurements</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lung function tests&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Airway hyperresponsiveness measurements&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Diagnostic tools employed to assess airway remodelling&#46;</p>"
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      1 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Cell types&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mediators&#47;proteins produced&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eosinophil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inflammation&#44; growth factor production &#40;TGF&#946;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGF&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cell&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mediators production &#40;histamine&#44; tryptase&#44; growth factors&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Histamine&#44; tryptase&#44; VEGF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epithelial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mediators production when injured&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGF&#946;&#44; EGF&#44; VEGF&#44; PGE2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Th2 cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subepithelial fibrosis and smooth muscle hyperplasia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-5&#44; IL-13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Regulatory t cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Down-regulate Th2 cells function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-10&#44; TGF&#946;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myofibroblast&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bronchial contraction&#44; ECM secretion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tenascin C&#44; fibronectine&#44; collagens I&#44; III and V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Most relevant cells involved in bronchial remodelling&#46;</p>"
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        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">MMP-9 &#40;matrix metalloproteinase-9&#41;&#46;</p>"
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Mediators&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Producing cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TGF&#946;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eosinophils&#44; regulatory T cells&#44; epithelial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibrosis&#44; smooth muscle proliferation&#44; mucus production&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EGF&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epithelial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epithelial cells migration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VEGF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cells&#44; epithelial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vascular remodelling&#44; mucus metaplasia&#44; smooth muscle proliferation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Th2 cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myofibroblasts activation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Th2 cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibrosis&#44; mucus production&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TNF&#945;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cells&#44; macrophages&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smooth muscle proliferation&#44; inflammatory cells activation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MMP-9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epithelial cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Degradation of extracellular matrix&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Histamine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cells&#44; basophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vascular permeability increment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tryptase&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cells&#44; basophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Smooth muscle proliferation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PGE2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epithelial cells&#44; smooth muscle cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Down-regulate smooth muscle and myofibroblasts proliferation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Most relevant mediators involved in bronchial remodelling&#46;</p>"
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      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
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              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:1 [
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            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "S&#46;T&#46; Holgate"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                        ]
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                    ]
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              ]
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            2 => array:3 [
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                      "autores" => array:1 [
                        0 => array:2 [
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                          "issn" => "01406736"
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            3 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "K&#46;F&#46; Chung"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1513/pats.200504-028SR"
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                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;J&#46; Evans"
                            1 => "L&#46;S&#46; Van Winkle"
                            2 => "M&#46;V&#46; Fanucchi"
                            3 => "C&#46;G&#46; Plopper"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Extracellular matrix and airway smooth muscle interactions&#58; a target for modulating airway wall remodelling and hyperresponsiveness&#63;"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "T&#46; Tran"
                            1 => "A&#46;J&#46; Halayko"
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                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1139/Y07-050"
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                        "fecha" => "2007"
                        "volumen" => "85"
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                      "titulo" => "Induction of angiogenesis by airway smooth muscle from patients with asthma"
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                          "autores" => array:6 [
                            0 => "D&#46;E&#46; Simcock"
                            1 => "V&#46; Kanabar"
                            2 => "G&#46;W&#46; Clarke"
                            3 => "K&#46; Mahn"
                            4 => "C&#46; Karner"
                            5 => "B&#46;J&#46; O&#8217;Connor"
                          ]
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                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1164/rccm.200707-1046OC"
                      "Revista" => array:6 [
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                        "fecha" => "2008"
                        "volumen" => "178"
                        "paginaInicial" => "460"
                        "paginaFinal" => "468"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18556625"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Saetta"
                            1 => "P&#46; Maestrelli"
                            2 => "G&#46; Turato"
                            3 => "C&#46;E&#46; Mapp"
                            4 => "G&#46; Milani"
                            5 => "F&#46; Pivirotto"
                          ]
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                    ]
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                    0 => array:2 [
                      "doi" => "10.1164/ajrccm.151.2.7842211"
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                        "fecha" => "1995"
                        "volumen" => "151"
                        "paginaInicial" => "489"
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              "identificador" => "bib0045"
              "etiqueta" => "9"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Endobronchial Biopsy Workshop&#46; Methods for the assessment of endobronchial biopsies in clinical research&#58; application to studies of pathogenesis and the effect of treatment"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
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                            2 => "S&#46; Wenzel"
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                    0 => array:2 [
                      "doi" => "10.1164/rccm.200202-150WS"
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                        "fecha" => "2003"
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                        "paginaInicial" => "S1"
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                        "link" => array:1 [
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                      "titulo" => "Tools used to measure airway remodelling in research"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46; Bergeron"
                            1 => "M&#46;K&#46; Tulic"
                            2 => "Q&#46; Hamid"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1183/09031936.00019906"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Respir J"
                        "fecha" => "2007"
                        "volumen" => "29"
                        "paginaInicial" => "596"
                        "paginaFinal" => "604"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17329494"
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Article information

ISSN: 03010546
Original language: English

DOI:10.1016/j.aller.2011.11.002

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Year/Month	Html	Pdf	Total

2024 November	5	0	5
2024 October	53	16	69
2024 September	64	15	79
2024 August	54	9	63
2024 July	72	18	90
2024 June	52	14	66
2024 May	51	7	58
2024 April	49	10	59
2024 March	71	7	78
2024 February	93	21	114
2024 January	81	27	108
2023 December	71	27	98
2023 November	82	21	103
2023 October	120	22	142
2023 September	75	10	85
2023 August	57	9	66
2023 July	68	6	74
2023 June	71	8	79
2023 May	120	13	133
2023 April	97	15	112
2023 March	85	13	98
2023 February	87	23	110
2023 January	55	14	69
2022 December	44	3	47
2022 November	43	21	64
2022 October	32	11	43
2022 September	40	24	64
2022 August	32	11	43
2022 July	35	19	54
2022 June	31	10	41
2022 May	19	19	38
2022 April	27	20	47
2022 March	42	19	61
2022 February	34	8	42
2022 January	29	8	37
2021 December	20	14	34
2021 November	33	13	46
2021 October	50	8	58
2021 September	28	14	42
2021 August	23	12	35
2021 July	19	11	30
2021 June	38	9	47
2021 May	33	8	41
2021 April	66	36	102
2021 March	24	6	30
2021 February	26	16	42
2021 January	24	12	36
2020 December	2	4	6
2020 November	0	1	1
2020 October	0	2	2
2020 September	0	2	2
2020 August	0	1	1
2020 July	0	2	2
2020 April	0	1	1
2020 March	0	1	1
2020 February	0	4	4
2020 January	0	9	9
2019 December	0	11	11
2019 November	0	1	1
2019 October	0	1	1
2019 September	0	2	2
2019 August	0	2	2
2019 July	0	7	7
2019 June	0	31	31
2019 May	0	38	38
2019 April	0	21	21
2019 March	0	2	2
2019 February	0	6	6
2019 January	0	3	3
2018 December	0	5	5
2018 September	0	1	1
2018 August	0	1	1
2018 July	0	1	1
2018 June	0	5	5
2018 February	5	3	8
2018 January	11	3	14
2017 December	2	2	4
2017 November	17	3	20
2017 October	5	5	10
2017 September	16	1	17
2017 August	8	8	16
2017 July	8	2	10
2017 June	26	5	31
2017 May	27	10	37
2017 April	17	4	21
2017 March	11	54	65
2017 February	5	8	13
2017 January	10	1	11
2016 December	21	8	29
2016 November	22	3	25
2016 October	38	7	45
2016 September	29	6	35
2016 August	17	6	23
2016 July	15	4	19
2016 June	25	10	35
2016 May	10	7	17
2016 April	22	12	34
2016 March	15	6	21
2016 February	17	12	29
2016 January	18	13	31
2015 December	13	8	21
2015 November	10	6	16
2015 October	16	8	24
2015 September	7	3	10
2015 August	11	4	15
2015 July	9	2	11
2015 June	9	2	11
2015 May	5	1	6
2015 April	15	9	24
2015 March	7	5	12
2015 February	24	1	25
2015 January	19	3	22
2014 December	22	6	28
2014 November	12	9	21
2014 October	17	5	22
2014 September	27	6	33
2014 August	14	3	17
2014 July	5	1	6
2014 June	5	2	7
2014 May	11	4	15
2014 April	9	6	15
2014 March	33	12	45
2014 February	29	6	35
2014 January	32	10	42
2013 December	27	10	37
2013 November	27	9	36
2013 October	58	13	71
2013 September	46	8	54
2013 August	35	12	47
2013 July	47	10	57
2013 June	7	3	10
2013 May	19	4	23
2013 April	18	9	27
2013 March	12	5	17
2013 February	8	9	17
2013 January	13	3	16
2012 December	7	3	10
2012 November	2	3	5
2012 October	1	2	3
2012 September	1	1	2
2012 March	710	0	710

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Allergologia et Immunopathologia is no longer published on Elsevier since the 2021 year.Transferred to Codon Publications

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