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Asthma is a chronic airway inflammatory disease that is associated with pulmonary remodelling of respiratory tissue. During asthma, lung structure changes due to persistent inflammation and causes obstruction of the air flow, which leads to a paradoxical hypoxic condition in the affected pulmonary tissue. Angiogenesis, which is one of the main components of the remodelling process, is mainly regulated by the vascular endothelial growth factor (VEGF), although other less influential factors are also involved. It is known that VEGF is up-regulated by hypoxia inducible factor 1 (HIF-1) during hypoxia. The transcription factor HIF-1 is a dimeric protein composed of two subunits: HIF-1α (inducible by hypoxia) and HIF-1β (constitutive). HIF-1 activates the transcription of genes during hypoxia by translocating to the nucleus and binding to hypoxia response elements (HREs) on the promoter regions of target genes. Recently the expression of HIF has been documented during angiogenesis in lung remodelling during asthma, thus suggesting that it may play a role in this process. The objective of this review is to give to the reader an overview of the literature in hypoxia and its role in remodelling and the pathogenesis of asthma. [ABSTRACT FROM AUTHOR]

Background It has been argued that a reduction in the Western diet of anti-inflammatory unsaturated lipids, such as n-3 polyunsaturated fatty acids, has contributed to the increase in the frequency and severity of allergic diseases. Objective We investigated whether feeding milk fat enriched in conjugated linoleic acid and vaccenic acids (VAs) (‘enriched’ milk fat), produced by supplementing the diet of pasture-fed cows with fish and sunflower oil, will prevent development of allergic airway responses. Methods C57BL/6 mice were fed a control diet containing soybean oil and diets supplemented with milk lipids. They were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 14 and 28, and challenged intranasally with OVA on day 42. Bronchoalveolar lavage fluid, lung tissues and serum samples were collected 6 days after the intranasal challenge. Results Feeding of enriched milk fat led to marked suppression of airway inflammation as evidenced by reductions in eosinophilia and lymphocytosis in the airways, compared with feeding of normal milk fat and control diet. Enriched milk fat significantly reduced circulating allergen-specific IgE and IgG1 levels, together with reductions in bronchoalveolar lavage fluid of IL-5 and CCL11. Treatment significantly inhibited changes in the airway including airway epithelial cell hypertrophy, goblet cell metaplasia and mucus hypersecretion. The two major components of enriched milk fat, cis-9, trans-11 conjugated linoleic acid and VA, inhibited airway inflammation when fed together to mice, whereas alone they were not effective. Conclusion Milk fat enriched in conjugated linoleic and VAs suppresses inflammation and changes to the airways in an animal model of allergic airway disease. [ABSTRACT FROM AUTHOR]

Background Occupational asthma (OA) may cause alterations of airways with inflammation and remodelling after cessation of exposure. Although the long-term clinical, functional and induced sputum sequelae have been examined in workers removed from exposure, the long-term pathological outcomes are unknown. Objective We aimed to investigate whether airway inflammation and remodelling were present in bronchial biopsies of subjects with prior OA but without evidence of persisting asthma at a mean interval of 14 years after cessation of exposure. Methods Ten clinically and functionally asymptomatic subjects with a prior diagnosis of OA were recruited and underwent bronchoscopy, bronchoalveolar lavage and bronchial biopsy. Comparisons were made with biopsies from normal control subjects. Epithelial detachment, epithelial metaplasia, mucous gland and airway smooth muscle (ASM) areas as well as the distance between the epithelium and ASM were measured by image analysis. The amount of collagen present was assessed by van Gieson staining. The numbers of TGF-β1- and eosinophil cationic protein (ECP)-positive cells were evaluated by specific immunostaining. Results Statistically significant increases were found in the numbers of TGF-β1- and ECP-positive cells and in the amount of subepithelial fibrosis present in the biopsies of subjects with prior OA compared with control biopsies. The distance between the epithelium and ASM was significantly reduced in the OA group. Increases in epithelial metaplasia, ASM mass, mucous gland numbers, collagen deposition and eosinophilia in the OA group were not statistically significant. There was no evidence of ongoing inflammation in the group with prior OA as assessed by the number of T lymphocytes present. Conclusion Some aspects of airway inflammation and remodelling persist in subjects with prior OA long after cessation of exposure even in the absence of clinical, sputum and functional abnormalities. These findings are relevant to the assessment of long-term sequelae in subjects with OA when reviewed after cessation of exposure. [ABSTRACT FROM AUTHOR]

Abstract: Bronchial asthma can be characterized by some significant changes in airway blood vessels, which may contribute to airway remodelling. Despite the clinical and functional consequences of bronchial microvascular remodelling in asthma, up to now, little data have been published on the therapeutic approach to this phenomenon. Corticosteroids are the only anti-asthma drugs that act positively on the three aspects of bronchial vascular remodelling: angiogenesis, dilatation and permeability. Modest positive effects of treatments with β2-agonists and leukotrienes receptor antagonists on bronchial microcirculatory changes have been reported. In the future, agents that specifically inhibit angiogenesis could represent a novel approach for positively acting on bronchial microvascular changes in chronic inflammatory airway diseases, such as chronic bronchitis and asthma. [Copyright &y& Elsevier]

Abstract: Airway remodelling refers to the structural changes that occur in the airway wall in asthma. These include epithelial hyperplasia and metaplasia, subepithelial fibrosis, muscle cell hyperplasia and angiogenesis. These structural changes result in thickening of the airway wall, airway hyperresponsiveness (AHR), and a progressive irreversible loss of lung function. The precise sequence of events that take place during the remodelling process and the mechanisms regulating these changes remain poorly understood. It is thought that airway remodelling is initiated and promoted by repeated episodes of allergic inflammation that damage the surface epithelium of the airway. However, other mechanisms are also likely to contribute to this process. Moreover, the interrelationship between airway remodelling, inflammation and AHR has not been clearly defined. Currently, there are no effective treatments that halt or reverse the changes of airway remodelling and its effects on lung function. Glucocorticoids have been unable to eliminate the progression of remodelling changes and there is limited evidence of a beneficial effect from other available therapies. The search for novel therapies that can directly target individual components of the remodelling process should be made a priority. In this review, we describe the current understanding of the airway remodelling process and the mechanisms regulating its development. The impact of currently available asthma therapies on airway remodelling is also discussed. [Copyright &y& Elsevier]

Background Rhinoviruses (RV), the major trigger of acute asthma exacerbations, are able to infect bronchial epithelium and induce production of pro-inflammatory, but also angiogenic and pro-fibrotic mediators. Fluticasone propionate (FP) and salmeterol (S) are clinically effective and act synergistically in controlling persistent asthma; however, their effect on virus-associated asthma is less clear. Aim The aim of this study was to assess the individual and combined effects of FP and S on RV-induced epithelial production of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). Methods Bronchial epithelial cells (BEAS-2B) were exposed in vitro to RV and were subsequently treated with FP and S, at physiologically relevant concentrations, alone or in combination. VEGF and FGF-2 were measured in the supernatants of these cultures using ELISA. Results FP was able to reduce RV-induced VEGF production in a dose-dependent manner. S also induced a smaller reduction; addition of both factors inhibited VEGF synergistically. FGF-2 production was not inhibited by either FP or S alone, but was significantly reduced when both substances were present in the culture. Conclusion This study demonstrates that FP and S may synergistically inhibit the production of angiogenic and/or pro-fibrotic factors that are induced after RV infection of BEAS-2B and are implicated in airway remodelling, suggesting that this combination may represent an important therapeutic option on virus-induced asthma. [ABSTRACT FROM AUTHOR]

Anatomical dead space measured by the Fowler method (VDF) is the sum of 2 serial volume compartments (VDF = VDp1 + VDp2). VDF has been shown to increase linearly with end-inspiratory lung volume (EILV) and the gradient of the relationship (ΔVDF) has been used as an index of airway distensibility. The aim of this study was to partition VDF into its serial compartments VDp1 and VDp2 to test the hypothesis that, given the greater distensibility of distal airways, VDp2 would demonstrate greater volume dependence than VDp1. The relationships between each measure of VD (VDF, VDp1, and VDp2) and EILV were studied in 16 healthy subjects and 16 mildly asthmatic subjects. Significant (p < 0.05) linear relationships were obtained between each measure of VD and EILV in both subject groups. Changes in VDp1 with EILV (ΔVDp1) accounted for 78.6% ± 5.6% (mean ± SEM) and 72.6% ± 6.3% of ΔVDF in the healthy and asthmatic groups, respectively. ΔVDp1 was greater in the healthy subjects than in asthmatic subjects (18.4 versus 13.1 mL/L, p = 0.005). We conclude that in both asthmatic and healthy subjects, the major component of ΔVDF was ΔVDp1 and not ΔVDp2, as originally hypothesized. We believe our results are reflecting the degree of asynchronous airway emptying. [ABSTRACT FROM AUTHOR]

Summary: With the rising world burden of asthma, it is crucial to define the early events that lead to chronic inflammation and airway remodelling. Chronic airway inflammation appears to be the culmination of both local epithelial dysfunction and a more generalised immune dysregulation that results in allergic predisposition. A number of antenatal and early postnatal events may contribute to this. However, although a systemic propensity for allergic responses (typically food allergy) frequently pre-exists in children who go on to develop asthma, there is still uncertainty over whether epithelial changes occur as a primary event or whether these are consequent to this evolving systemic propensity for type 2 T-helper cell allergic responses. Many children with asthma already show many of the features of chronic airway inflammation, with epithelial desquamation, inflammatory cell infiltrates, subepithelial basement membrane thickening and fibrosis, goblet cell hyperplasia and smooth muscle hypertrophy. These changes can be evident before asthma is diagnosed, and there is also evidence that airway inflammation and early remodelling can progress in a subclinical state. New studies suggest that early airway damage is irreversible and that subsequent lung function is ‘set’ in the first years of life. These observations highlight the need to identify affected or at-risk children early and to develop interventions that can abort or prevent ongoing airway inflammation and remodelling. [Copyright &y& Elsevier]

Summary: Background: Exacerbation is one of the most significant problems in patients with asthma. Although subpopulation of patients is more susceptible to exacerbations than others, which clinical features characterise susceptibility to exacerbation are not well understood. Methods: Consecutive non-smoking adult patients with asthma who had multiple exacerbations (ME) despite regular maintenance treatment were compared with those who had at most single exacerbation as control during the previous 1 year. Exacerbation of asthma is defined initiations or escalations of systemic corticosteroid as part of the management for aggravated asthma condition. Results: Patients with ME (, male: 6, mean age: 46.7 years) were characterised by intensive current maintenance treatment (dose of inhaled corticosteroid; 1037.5±452.8 vs 621.6±257.3μg, , proportion of oral corticosteroid users; 28.1% vs 2.7%, ), severe episodes of exacerbation (asthma-related hospitalisations; 71.9% vs 23.4%, , arrival on ambulance; 37.5% vs 8.1%, ), concomitant chronic sinusitis (34.4% vs 10.8%, ) and intolerance to non-steroidal anti-inflammatory drugs (NSAIDs) (34.4% vs 5.4%, ) in comparison with controls (, male:11, mean age:44.4). Pulmonary function in patients with ME was characterised by persistent airflow limitation and reduced reversibility. Conclusion: Patients with ME are at increased risk for severe exacerbation despite more intensive maintenance anti-inflammatory treatment. Persistent irreversible airflow limitation and complications of chronic sinusitis and/or NSAIDs intolerance are characteristics to this subpopulation. [Copyright &y& Elsevier]

Abstract: As a consequence of long-term exposure to inflammatory mediators, the airways of asthmatics become remodelled. Airway fibrosis becomes apparent, with thickening of the lamina recticularis and increased interstitial matrix deposition being typical features of an asthmatic airway. Mucus hypersecretion occurs, airway smooth muscle mass is increased and neovascularization is evident in the subepithelial mucosa. As development of a remodelled airway is correlated with deterioration of lung function in asthmatics, there is an urgent need for therapies that reduce airway inflammation and reverse structural changes in a remodelled airway. However, in order to design efficacious anti-remodelling agents we first need a greater understanding of the molecular mechanism/s underlying the development of airway remodelling. To date, however, most studies have primarily focused on the transcriptional regulation of genes that promote airway remodelling. Post-transcriptional mechanisms, such as control of mRNA stability, remain largely unexplored. Levels of cellular mRNA transcripts are regulated by controlling the rate at which the mRNA decays, thus investigation into the mechanisms underlying mRNA stability in asthma are of critical importance. Therefore, this review will present an overview of the control of mRNA stability and examine how mRNA stability may play a role in the development of airway remodelling in asthma. [Copyright &y& Elsevier]

Background Asthma is accepted as a disease characterized by airway inflammation, with evidence that airway structural changes, or ‘remodelling’ occurs. There are few studies relating airway physiology, inflammation and remodelling, however. We have carried out a study of inter-relationships between airway inflammation, airway remodelling, reticular basement membrane (RBM) thickening, and bronchial hyper-reactivity (BHR), before and after high-dose inhaled corticosteroid (fluticasone propionate 750 μg b.d.), in a group of relatively mild but symptomatic, steroid naïve asthma patients. Methods Double-blind, randomized, placebo-controlled, parallel group study of inhaled corticosteroid (ICS) in 35 asthmatics, with bronchoalveolar lavage (BAL) and airway endobronchial biopsy (EBB) for inflammatory cell profiles and EBB for airway remodelling carried out at baseline, 3 and 12 months. Results At baseline RBM thickening was related to BAL mast cells and EBB eosinophil counts. In turn baseline log EBB EG2 eosinophil count, log%BAL epithelial cells and log RBM thickness explained 55% of the variability in BHR. Conclusion We provide new information that airway inflammation, remodelling, and BHR in asthma are inter-related and improved by ICS therapy. Our data potentially support the need for early and long-term intervention with ICS even in relatively mild asthmatics, and the need to further assess the potential merit of longitudinal BHR testing in management of some patients, as this may reflect both airway inflammation and remodelling. [ABSTRACT FROM AUTHOR]

1. Severe persistent asthma is accompanied by structural changes in the airway, referred to as remodelling. The mechanisms driving airway remodelling are poorly understood. 2. Transforming growth factor (TCF)-β is increased in the airways of patients with asthma. Many of the effects of TGF-β are mediated by connective tissue growth factor (CTGF). 3. Overexpression of CTGF is linked to many fibrotic diseases, but its exact role in airway remodelling is unknown. 4. Connective tissue growth factor mediates cell adhesion, migration, proliferation, survival, extracellular matrix synthesis and has a role in angiogenesis. 5. Current asthma therapies do not inhibit CTGF induction. 6. Understanding the mechanisms underlying the role of CTGF in airway remodelling may lead to new therapeutic strategies for asthma. [ABSTRACT FROM AUTHOR]

Background There is increasing in vitro evidence to support a role for vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, as a mediator of fibrosis associated with neovascularization. Objective We tested the hypothesis that VEGF is involved both in increased airway mucosal vascularity and in the subepithelial fibrosis of asthmatic patients. Methods Bronchial biopsies were performed in 24 asthmatic patients and eight healthy controls. Immunostaining, using computerized image analysis, was performed using monoclonal antibodies against VEGF+ cells, type IV collagen, to outline the basement membrane thickness, and tryptase and EG2, to identify mast cells and eosinophils, respectively. Results The counts of VEGF+ cells ( P<0.05), mast cells and EG2+ cells (both P<0.01) were higher in asthmatics than in controls. The number of vessels, the vascular area in the lamina propria, and the basement membrane thickness were significantly higher in asthmatics than in healthy volunteers ( P<0.01). Moreover, in asthmatic patients, the number of VEGF+ cells was significantly related to the number of vessels ( P<0.01), to mast cells ( P<0.01) and to basement membrane thickness ( P<0.01). A colocalization study also revealed that mast cells were a relevant cellular source of VEGF. High doses of inhaled fluticasone propionate significantly reduced VEGF+ cells ( P<0.05), vessel number ( P<0.05), vascular area ( P<0.05) and basement membrane thickness ( P<0.05) in a subgroup of asthmatic patients. Conclusions This study shows that VEGF, in addition to being involved in the vascular component of airway remodelling, may play a role in the thickening of the basement membrane in asthma. [ABSTRACT FROM AUTHOR]

Pohunek P, Warner JO, Turzíková J, Kudrmann J, Roche WR. Markers of eosinophilic inflammation and tissue re-modelling in children before clinically diagnosed bronchial asthma.Pediatr Allergy Immunol 2005: 16: 43–51.© 2005 Blackwell MunksgaardChronic inflammatory changes in the bronchial mucosa have been well documented in patients with established asthma. Much less is known of the changes, which occur in the airways of children early in the evolution of their disease with most of the information based on indirect markers of inflammation only. We evaluated markers of inflammation and tissue re-modelling in bronchial biopsies from children with early respiratory symptoms before a clear clinical diagnosis of bronchial asthma could be made. We examined bronchial biopsies performed in 27 children between the ages of 1.2 and 11.7 yr who were bronchoscoped for a clinical indication because of recurrent or chronic respiratory symptoms. The patients were re-evaluated 22–80 months after the original bronchoscopy to determine whether or not they had subsequently developed bronchial asthma. There were more eosinophils in the bronchial mucosa (129.4 vs. 19.1 cells/mm2 of lamina propria, p < 0.001) and the thickness of the subepithelial lamina reticularis was greater (4.65 vs. 3.72 μm, p = 0.044) in children with bronchial asthma diagnosed at follow-up, compared with the children who did not progress to asthma. Eosinophilic inflammation and airway re-modelling occur early in the natural history of bronchial asthma and are present even before asthma would be diagnosed based on clinical symptoms. Recognition of these changes and their significance for clinical disease should emphasize the need for timely detection and diagnosis of asthma in children to facilitate the early introduction of anti-asthma therapy. [ABSTRACT FROM AUTHOR]

Abstract: Airway mucosal changes have been reported in chronic cough. In cough variant asthma and in eosinophilic bronchitis, there is evidence of eosinophil infiltration and sub-basement membrane thickening. In non-asthmatic cough, an increase of bronchoalveolar mast cells, mucosal mononuclear cells, and epithelial shedding have been reported. In a more recent study, evidence of airway wall remodelling has been observed in both asthmatic and non-asthmatic cough, such as an increase in sub-basement membrane thickness, goblet cell area, vascularity and vessel size. Smooth muscle area was increased in non-asthmatic coughers. Heightened cough sensitivity in non-asthmatic coughers was related to the degree of goblet cell hyperplasia and epithelial shedding. Cough reflex may be heightened by increased production of growth factors that might be further enhanced by the physical effects of cough on the airways. Mast cells may participate in the cough pathophysiology through release of growth factors as well as tussive mediators. Changes in the airway wall mucosa and epithelium may be important in the pathogenesis of cough receptor sensitization. [Copyright &y& Elsevier]

Chronic rejection is a major problem for all lung transplant programmes, which is functionally manifested by fixed airflow limitation, Bronchiolitis Obliterans Syndrome (BOS). The inclusion of a Pre-BOS category, BOS0∼p, in newly revised guidelines, recognizes the potential importance of early changes. We have previously demonstrated reticular basement membrane (Rbm) thickening in clinically stable lung transplant recipients free from BOS. The present study extends this, testing the hypothesis that inhaled corticosteroid (ICS) therapy will lead to a decrease in Rbm thickness in lung transplant recipients.A parallel group, bronchoscopic intervention study of clinically stable lung allograft recipients, free from BOS, but with evidence of airway inflammation. Following baseline assessment of Rbm thickening, subjects were randomized to 3 months of either chlorofluorocarbon-driven beclomethasone diproprionate (BDP) 400 μg b.i.d., or a formulation designed to yield at least an equivalent dose, hydrofluoroalkane-driven BDP, 200 μg b.i.d.Three months treatment with a moderate dose of ICS, including a formulation designed for preferential small airway deposition, had no effect on Rbm thickening (13±3 vs. 14±5 μm post-ICS).Our data would suggest that airway remodelling can occur early in lung allografts and is not affected by moderate dose ICS therapy. Longitudinal studies are required to describe the pathophysiological processes involved in BOS, and specifically to elucidate potential relationships between airway remodelling, airflow obstruction and allograft failure. [ABSTRACT FROM AUTHOR]

Increased airway smooth muscle mass is a pathological feature that asthma and chronic obstructive pulmonary disease (COPD) have in common. This increase has gained renewed interest in view of recent developments showing that airway smooth muscle, instead of solely being a contractile partner, is capable of interacting dynamically with its environment, especially under inflammatory conditions. Airway smooth muscle cells are able to proliferate, to migrate, and to secrete chemokines, cytokines, extracellular matrix proteins and growth factors, and most importantly, to adapt to these functions by changing its phenotype from contractile to proliferative/synthetic. Conversely, switching to a (hyper)contractile phenotype may also occur. A vast number of inflammatory stimuli regulate these functions and exert their effects via excitatory Gq or Gi-coupled receptors. Since acetylcholine activates muscarinic M2 and M3 receptors in the airway smooth muscle cell membrane, which are coupled to Gi and Gq proteins, respectively, and since acetylcholine release may be enhanced in airway inflammation, a pathophysiological role of acetylcholine related to the above processes and exceeding contraction could be envisaged. In this review, evidence in favour of this hypothesis, based on recent data that show a role for muscarinic receptors in modulating airway smooth muscle proliferation, contractility and contractile protein expression is discussed. Based on these findings, we postulate that endogenous acetylcholine contributes to airway remodeling in asthma and COPD. [Copyright &y& Elsevier]

Corticosteroids play an important role in inflammation and remodelling of airways and are considered an important therapeutic target in asthma. Inflammation in asthma is characterized by a dysregulation of eosinophil apoptosis and of markers of airways remodelling. We evaluated the ability of flunisolide to inhibit in vitro the release of metalloproteinases-9 (MMP-9), tissue inhibitor metalloproteinases-1 (TIMP-1), transforming growth factor (TGF- β) and fibronectin by sputum cells (SC) as well as to induce sputum eosinophil apoptosis. The SC, isolated from induced sputum samples of 12 mild-to-moderate asthmatics, were cultured for 24 h in the presence or absence of flunisolide (1, 10 and 100 μM). The release of mediators was assessed by enzyme-linked immunosorbent assay (ELISA) whereas apoptosis was studied by TUNEL technique. Flunisolide (10 μM) significantly reduced MMP-9 and TIMP-1 ( P = 0.0011 and P < 0.0001 respectively) and increased MMP-9/TIMP-1 molar ratio ( P = 0.004). In addition, flunisolide decreased TGF- β and fibronectin release by SC ( P = 0.006; and P < 0.0001 respectively) and increased eosinophil apoptosis ( P < 0.001). These results demonstrate that flunisolide may play an important role in the inhibition of airway inflammation and remodelling, by promoting the resolution of eosinophilic inflammation and by inhibiting the release of MMP-9, TIMP-1, TGF- β and fibronectin. [ABSTRACT FROM AUTHOR]

Inflammatory gene expression in airway smooth muscle may be influenced by its inflammatory milieu. We analysed the gene expression profile of airway smooth muscle cells cultured from human airways exposed to a pro-inflammatory cytokine, interleukin-1β, a T helper-2 cytokine, interleukin-13, and to a growth factor, transforming growth factor (TGF)β1 (10 ng/ml each) after 4 and 24 h using the Affymetrix GeneChip 95A array which detects ∼12,500 genes and expression sequence tags (ESTs). Airway smooth muscle cells were responsive to each cytokine with distinctive patterns of gene expression for cytokines, chemokines, adhesion and signalling proteins, and transcription factors. Interleukin-1β induced the highest number of genes such as cytokines/chemokines including interleukin-8, growth-related oncogene (GRO)-α, -β and -γ, epithelial neutrophil activating protein (ENA)-78, monocyte chemotactic protein (MCP)-1, -2 and -3 and eotaxin. Using quantitative real-time reverse transcription-polymerase chain reaction, the expression of GRO-α, -β and -γ, interleukin-8 and eotaxin by interleukin-1β was confirmed, with good correlation with microarray data. Transforming growth factor (TGF)β1 induced other growth factors such as connective tissue growth factor (CTGF), vascular endothelial growth factor (VEGF), insulin growth factor (IGF) and many structural and extracellular matrix proteins. Interleukin-13 was the weakest inducer, with stimulation of eotaxin and genes of unknown function. While many genes were co-regulated at 4 and 24 h, there were also differences in expression patterns. Interleukin-1β induces a predominantly pro-inflammatory profile while TGFβ1 can be linked to proliferative and matrix changes. The rich profile of mediators, growth factors and signalling molecules released from airway smooth muscle depends on the inflammatory milieu. [Copyright &y& Elsevier]

Airway remodelling is a feature of chronic asthma comprising smooth muscle hypertrophy and deposition of extracellular matrix (ECM) proteins. Matrix metalloproteinases (MMPs) breakdown ECM, are involved in tissue remodelling and have been implicated in airway remodelling. Although mesenchymal cells are an important source of MMPs, little data are available on airway smooth muscle (ASM) derived MMPs. We therefore investigated MMP and tissue inhibitor of metalloproteinase (TIMP) production and activity in human ASM cells.MMPs and TIMPs were examined using quantitative real-time RT–PCR, Western blotting, zymography and a quench fluorescence (QF) assay of total MMP activity.The most abundant MMPs were pro-MMP-2, pro- MMP-3, active MMP-3 and MT1-MMP. TIMP-1 and TIMP-2 expression was low in cell lysates but high in conditioned medium. High TIMP secretion was confirmed by the ability of ASM-conditioned medium to inhibit recombinant MMP-2 in a QF assay. Thrombin increased MMP activity by activation of pro-MMP-2 independent of the conventional smooth muscle thrombin receptors PAR 1 and 4.In conclusion, ASM cells express pro-MMP-2, pro and active MMP-3, MMP-9 and MT1-MMP. Unstimulated cells secrete excess TIMP 1 and 2, preventing proteolytic activity. MMP-2 can be activated by thrombin which may contribute to airway remodelling.British Journal of Pharmacology (2004) 142, 1318–1324. doi:10.1038/sj.bjp.0705883 [ABSTRACT FROM AUTHOR]

Airway inflammation and remodelling are characteristic features of chronic asthma. To elucidate the role of interleukin (IL)-6 in airway responses to chronic antigen exposure. We compared airway inflammation, subepithelial collagen deposition, cytokine mRNA expression, and airway responsiveness between IL-6-deficient and wild-type (WT) mice following sensitization and repeated exposure to ovalbumin (OVA) three times a week for 8 weeks. The repeated exposure to OVA induced infiltration of eosinophils, neutrophils, and lymphocytes into the airway, and caused thickening of the basement membrane and subepithelial fibrosis. IL-6-deficient mice exhibited more pronounced infiltration of these cells, a thinner basement membrane, and decreased subepithelial fibrosis, compared with WT mice. The repeated OVA exposure increased expression of IL-4, IL-13, eotaxin, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β1 mRNA in WT mice. Among these factors, expression of IL-13 and MCP-1 mRNA was further enhanced in IL-6-deficient mice, compared with WT mice. However, both WT and IL-6-deficient mice exhibited similar levels of airway responsiveness to increasing doses of methacholine, even after repeated exposure to OVA. These results suggest that IL-6 has dual roles in the chronic phase of asthma: down-regulation of inflammatory cell infiltration and enhancement of airway remodelling. [ABSTRACT FROM AUTHOR]

Allergen exposure of sensitised lungs produces bronchial hyperresponsiveness in vivo associated with airway inflammation and remodelling. It is unclear if hyperresponsiveness is also present in airways in vitro under similar conditions of drug provocation as carried out in vivo, and at different times after allergen-challenge. This study records responsiveness of individual airway segments to acetylcholine (ACh) in sensitised bronchi after instillation of allergen (ovalbumin, OA). Airway histology and sensitivity and maximum effects to ACh were recorded 1, 24 and 72 h and 1 week after OA. OA-instilled airways exhibited eosinophilia and epithelial proliferation. Physiological recordings showed no change in maximum contractions of airway segments to acetylcholine placed in the airway lumen except at 24 h where they were reduced. In contrast maximum contractions to ACh to the airway adventitia were reduced at all times except 1 week, with the greatest change occurring at 24 h. There were no changes in airway sensitivity to either route of ACh in OA-instilled airways but the difference in sensitivity to adventitial and lumenal ACh was reduced. Results show that allergen does not produce hyperresponsiveness at the airway wall but it may alter an interaction between airway smooth muscle and other structural components of the airway. [Copyright &y& Elsevier]

Asthma is characterized by an eosinophilic inflammation and a subepithelial fibrosis in the airways. Eosinophils contain several cytotoxic substances, such as eosinophil cationic protein (ECP), which can promote inflammation and cause tissue damage. This has generated the hypothesis that eosinophils may drive remodelling of extracellular matrix (ECM). To investigate the role of eosinophils we used an in vitro model for remodelling, the three-dimensional collagen gel contraction assay. Two sources of eosinophils were used in this study, isolated human peripheral eosinophils (purity > 95%) and stimulated [interleukin (IL)-5, IL-3 and granulocyte macrophage–colony stimulating factor (GM-CSF)] HL-60 clone 15 cells. Human eosinophils or HL-60 cells were cast together with human lung fibroblasts (HFL1) in type I collagen gels. Both types of eosinophils augmented fibroblast-mediated collagen gel contraction in a time and concentration-dependent manner. At 48 h, the gel area in HFL1/eosinophil co-culture was 46·5% ± 0·5 (mean ± s.e.m.) of initial area and in HFL1 culture 52·3% ± 0·1 ( P < 0·001). Respective figures for HFL1/stimulated HL-60 co-culture and HFL1 culture only were 44·1% ± 0·5 and 52·4% ± 0·4 ( P < 0·001). The release of ECP was increased when fibroblasts were cultured with eosinophils compared to eosinophils cultured alone. In addition, native ECP added to fibroblast gel cultures also augmented contraction. Our results suggest that eosinophils may interact with mesenchymal cells, promoting remodelling of ECM and that ECP constitutes one potential eosinophil-derived mediator driving this process. We conclude that this may be one important mechanism by which eosinophil–ECM interactions will lead to airway tissue remodelling in asthma. [ABSTRACT FROM AUTHOR]

Human airway smooth muscle cells (HASMC) contribute to the process of airway wall remodelling in asthma by virtue of their secretory functions. This study was performed to investigate the effectiveness of the commonly used steroids beclomethasone, budesonide and fluticasone in downregulating HASMC production of RANTES and IL-8.HASMC (n=5) were cultured from dissected bronchi using collagenase digestion. Confluent HASMC were exposed to TNFα and IL-1β (10 ng/ml) for 24 h. All stimulations were set with and without pre-treatment with beclomethasone, budesonide or fluticasone for 2 h at concentrations of 10−9–10−6 M. IL-8 and RANTES mRNA expression was assessed by RT-PCR and protein secretion was determined by ELISA.Pre-treatment with beclomethasone, budesonide or fluticasone reduced TNFα- and IL-1β-stimulated IL-8 and RANTES release from HASMC in a dose dependent manner. However, beclomethasone was 22–28% less effective than fluticasone and budesonide in inhibiting chemokine production. TNFα- and IL-1β-induced RANTES and IL-8 expression was reduced on the transcriptional level by pre-treatment with fluticasone and budesonide.The results suggest that the topical steroids fluticasone, budesonide and to a lesser extent beclomethasone may have beneficial effects on airway inflammation in asthma by reducing RANTES and IL-8-induced leukocyte infiltration into the airway wall. [Copyright &y& Elsevier]

Toluene diisocyanate (TDI)-induced asthma is an inflammatory disease of the airways characterized by airway remodelling due, at least in part, to an excess of extracellular matrix deposition in the airway wall. The ratio of matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) may be a marker of the balance between airway tissue destruction and repair. We determined whether an imbalance of the MMP-9 : TIMP-1 molar ratio is present before and/or after challenge with TDI. We used a murine model of TDI-induced asthma to evaluate the MMP-9 and TIMP-1 balance in the lung. The expression of MMP-9 and TIMP-1 mRNAs and proteins in the lungs increased at 7 h after TDI inhalation and continued for up to 72 h. Immunohistochemical and immunocytological analyses in the lungs of TDI-exposed mice revealed increases of immunoreactive MMP-9 and TIMP-1. There were significant correlations between the levels of MMP-9 or TIMP-1 and the number of neutrophils, lymphocytes, or eosinophils. The molar ratio of MMP-9/TIMP-1 significantly decreased at 7 h after TDI inhalation and continued up to 72 h. These data suggest that TDI-induced asthma may be associated with an imbalance between MMP-9 and TIMP-1, which could be useful as a marker of airway inflammation and airway remodelling in this disease. [ABSTRACT FROM AUTHOR]

Bronchial asthma remains a significant cause of mortality at all ages, despite the increased understanding of its pathogenesis and the range of drugs available for its treatment. Changes in therapeutic management can influence death rates and constant surveillance, combined with high-quality post mortem investigations, is essential. Disease severity, poor disease management and adverse psychosocial circumstances are all risk factors for asthma mortality. Bronchial asthma causes characteristic histological changes in the mucosa of the airways which are present even before the clinical diagnosis of asthma can be made. These include fibrous thickening of the lamina reticularis of the epithelial basement membrane, smooth muscle hypertrophy and hyperplasia, increased mucosal vascularity and an eosinophil-rich inflammatory cell infiltrate. In addition, mucoid plugging of the airway lumen is frequently associated with fatal asthma. The recognition of these changes can allow the diagnosis of asthma to be made for the first time at autopsy, in those cases where asthma goes undiagnosed in life. Acute severe asthma may be accompanied by pneumothorax and surgical emphysema of the mediastinum. Disorders which may mimic asthma include pulmonary embolism, chronic obstructive pulmonary disease and anaphylaxis, but careful post mortem examination and appropriate investigations should reveal the true cause of death. [ABSTRACT FROM AUTHOR]

Summary Background Role of mast cells in the development of allergen-induced airway remodelling has not been fully investigated in vivo . Objective To clarify the possible role of mast cells in the development of allergen-induced airway remodelling, we compared their responses of genetically mast cell-deficient mice, WBB6F1-W/Wv (c-kit mutant) and Sl/Sld (c-kit ligand mutant) mice with those of congenic normal mice in a murine model of allergic asthma. Methods Mice were sensitized to ovalbumin (OA) with alum, and exposed daily for 3 weeks to aerosolized OA. Twenty-four hours after the last inhalation, bronchial responsiveness to acetylcholine (Ach) was measured, and bronchoalveolar lavage (BAL), and biochemical and histological examinations were performed. Results In both sensitized mast cell-deficient mice, the degree of bronchial hyper-responsiveness to Ach, the number of inflammatory cells and the level of transforming growth factor-β1 in BAL fluid, IgE response and goblet cell hyperplasia in the epithelium after repeated allergen provocation were not significantly different from those of congenic mice. In contrast, subepithelial fibrosis, evaluated in the fibrotic area around the airways, observed in congenic mice after repeated allergen challenge was partially attenuated in both mast cell-deficient mice. In addition, the amount of hydroxyproline in the lung of mast cell-deficient mice was significantly lower than that of congenic mice. Furthermore, the decreased fibrotic area and amount of hydroxyproline in W/Wv mice was completely recovered by reconstitution of tissue mast cells with bone marrow-derived mast cells of congenic mice. Conclusion These findings suggest that mast cells play a partial role in the development of allergen-induced subepithelial fibrosis, although airway inflammation, epithelial remodelling and BHR caused by repeated allergen challenge are independent of mast cells, at least in this model. [ABSTRACT FROM AUTHOR]

Summary Background Local airway inflammation and airway remodelling are considered important in the clinical expression of allergic asthma. Objective The aim of this study was to compare airway inflammation and remodelling in nasal and bronchial mucosa of subjects with allergic rhinitis with or without asthma. Methods Four experimental groups were formed: allergic asthma and rhinitis (n = 19); allergic rhinitis, no asthma (n = 18); atopic subjects, no asthma, no rhinitis (n = 8) and non-allergic healthy control subjects (n = 16). Blood samples, nasal and bronchial biopsy specimens were collected during stable disease. Immunohistochemistry was performed for eosinophils (MBP), mast cells (CD117) and vascular endothelium (CD31). Epithelial loss, reticular basement membrane (RBM) thickness and subepithelial vascularity was assessed with a computer-assisted image analysis system. Results In nasal and bronchial mucosa, numbers of eosinophils were significantly higher in rhinitis patients with and without asthma than in asymptomatic atopics (P < 0.05) and controls (P ≤ 0.01). In bronchial mucosa, the RBM was significantly thickened in rhinitis patients with and without asthma compared to asymptomatic atopics (P < 0.05) and controls (P < 0.01), while in nasal mucosa no differences were seen. Patients with asthma and rhinitis had increased numbers of blood eosinophils (P = 0.05) and skin test reactivity (P = 0.01) compared to patients with rhinitis only. No significant differences could be found between the investigated groups with respect to serum IL-5 and eotaxin levels, the number of mucosal mast cells and the degree of epithelial loss and subepithelial vascularity. Epithelial desquamation was significantly increased in the bronchial mucosa compared to nasal mucosa, not only in asthmatics (P < 0.001), but also in atopics without asthma and rhinitis (P = 0.02). Conclusions This study shows that allergic inflammation, increased basement membrane thickness and... [ABSTRACT FROM AUTHOR]

Summary Background Therapeutic modalities of asthma have not been proved to be successful in reversing the already established chronic changes of airways. Objective We aimed to determine the impact of heat-killed Mycobacterium vaccae immunization, a potent Th1 stimulant, on chronic changes of asthma. Methods Newborn BALB/c mice were divided into three groups; mice in M. vaccae group received 107 colony-forming units (CFU)/50 µL of heat-killed M. vaccae subcutaneously on days 3, 14 and 42 before the development of chronic asthma model, whereas mice in control and chronic asthma groups received saline. Subsequently, mice in M. vaccae and chronic asthma groups were administered 10 µg/100 µL of ovalbumin (OVA) on days 43, 45, 47, 49, 51, 53 and 55 intraperitoneally, and 20 µg/10 µL of OVA on days 83, 86 and 89 intratracheally. Mice in control group received saline on the same days. Results Comparison of M. vaccae and chronic asthma groups showed statistically significant differences in goblet cell numbers, thickness of basement membrane and subepithelial smooth muscle of small, medium and large airways and epithelial thickness of medium airways. There was no significant difference between the control and M. vaccae groups except for goblet cell numbers of medium and large airways, and epithelial thickness of medium airways. Conclusion Results of our study suggested that immunization by M. vaccae of newborn mice would prevent some of the chronic changes of airways due to asthma. [ABSTRACT FROM AUTHOR]

Summary Background Airway remodelling in asthma such as subepithelial fibrosis is thought to be the repair process that follows the continuing injury as of chronic airway inflammation. However, how acute allergic inflammation causes tissue injury in the epithelial basement membrane in asthmatic airways remains unclear. Matrix metalloproteinases (MMPs) capable of degrading almost all of the extracellular matrix components have been demonstrated to be involved in cell migration through the basement membrane in vivo and in vitro . Objective We investigated the alterations of matrix construction and the role of MMPs in matrix degradation in the subepithelium during acute allergic airway inflammation. Methods Airway inflammation, the ultrastructure of the subepithelium and injury of types III and IV collagen in tracheal tissues from ovalbumin (OVA) -sensitized mice after OVA inhalation with or without the administration of tissue inhibitor of metalloproteinase-2 (TIMP-2) and dexamethasone were evaluated by cell counting in bronchoalveolar lavage (BAL) fluids, electron microscopy and immunohistochemistry, respectively. Results The disruption of the lamina densa and matrix construction and the decrease of the immunoreactivity for type IV collagen in subepithelium were observed in association with the accumulation of inflammatory cells in airways 3 days after OVA inhalation. This disorganization of the matrix components in the subepithelium, as well the cellular accumulation, was abolished by the administration of TIMP-2 and dexamethasone. The immunoreactivity for type IV collagen in the subepithelium in OVA-inhaled mice returned to the level of that in saline-inhaled mice 10 days after inhalation in association with a decrease of the cell numbers in the BAL fluid. The immunoreactivity for type III collagen was changed neither 3 nor 10 days after OVA inhalation. Conclusion These results suggest that epithelial basement membrane gets injured by, at least in part, MMPs as... [ABSTRACT FROM AUTHOR]

Summary Background Structural remodelling of airways in asthma that follows inflammation may be affected by surfactant protein D (SP-D)-mediated effects on the immune response. Objective To determine potential sites of SP-D interaction with the pulmonary immune response, we examined the distribution of immunoreactive SP-D in an experimental model of allergen-induced airway inflammation using immunohistochemistry, biochemical methods and in situ hybridization. Methods The experimental model used subcutaneous injection of ovalbumin in adult rats, which induced an airway response to inhaled nebulized ovalbumin. Three groups of rats (ovalbumin, ovalbumin + dexamethasone and saline) were challenged thrice weekly for 3 weeks. A fourth group of seven rats (naive) were taken from the same delivery of rats as the other groups. Lungs were then lavaged to determine total cell count, eosinophil count, ovalbumin-specific IgE by enzyme-linked immunosorbent assay and SP-D by immunoblot. Tissue samples were fixed and embedded, and sections were studied for the infiltration of eosinophils and for expression of SP-D protein by histochemistry and mRNA by in situ hybridization. Results Ovalbumin induced perivascular and peribronchiolar eosinophilia which could be prevented by dexamethasone treatment. In addition, the ovalbumin-specific IgE levels in serum and bronchoalveolar lavage fluid of ovalbumin-challenged animals were enhanced. Increased amount of SP-D in lavage and tissue, particularly in type II pneumocytes, in Clara cells and, surprisingly, in hyperplastic goblet cells of inflamed lungs was found. SP-D mRNA was detected in goblet cells as well as in type II pneumocytes and Clara cells. Dexamethasone treatment did not affect level of SP-D immunoreactivity. Conclusion SP-D accumulation is increased in this model of allergen-induced eosinophilia, both in upper and lower airways. The increase is unaffected by dexamethasone. [ABSTRACT FROM AUTHOR]

BackgroundPlatelet-derived growth factor A-chain (PDGF-A) is a potent connective tissue mitogen implicated in lung growth and development. PDGF-A may have a role in asthma through effects on fibroblasts and bronchial smooth muscle cells. ObjectiveTo test the hypothesis that there exist variations in the PDGF-A gene associated with the asthma phenotype. MethodsWe screened genomic DNA from normal and asthmatic subjects using single-stranded conformational polymorphism (SSCP) for mutations in the promoter and all seven exons of the gene. ResultsFour transition polymorphisms (three novel) were identified: one each in exons 3 and 4 (overall population allele frequencies 0.18 and 0.02, respectively) which did not alter the protein sequence, one in exon 4 (frequency 0.005) which resulted in a valine to isoleucine substitution, and one in intron 5 (frequency 0.5). The intron 5-sequence variant is close to the 3′ end of exon 5 but does not appear to affect alternative splicing of PDGF-A exon 6 RNA. The frequencies of the polymorphisms in exons 3 and intron 5 did not differ between the asthmatic and non-asthmatic subjects, but there was a significant frequency difference between Caucasian and African-American subjects for each of these polymorphisms (P = 0.03 and 0.003, respectively). ConclusionNo association was found between the sequence variants in the PDGF-A gene and the development of asthma. However, the allele frequency of some of the sequence variants differed between the Caucasian and African-American subjects. [ABSTRACT FROM AUTHOR]

Summary Dramatic changes to the architecture of the airway walls have been commonly described in the airways of patients with asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Much research has focused on how airway inflammation drives these structural changes, particularly in terms of the mechanisms/mediators that are involved, and a number of parallels are observed between the disease phenotypes. For example, the increased deposition of extracellular matrix (ECM) at focal sites in the airway wall is seen in asthma and all interstitial lung diseases that involve fibrosis. In addition, increased expression of a number of well characterized cytokines and growth factors, such as TGF-β and epidermal growth factor (EGF) have been demonstrated in these diseases. However, the role of the lesser-known cytokines, including the leukaemia inhibitory factor (LIF) and other members of the IL-6 family of cytokines in the pathogenesis of airway remodelling and fibrosis is largely unknown. However, the use of genetic manipulation in vivo and more specific inhibitors/antibodies in vitro has now provided increasing evidence to support the hypothesis that a complex interaction exists between these cytokines, ECM and integrins in regulating the function of both epithelial cells and fibroblasts. [ABSTRACT FROM AUTHOR]

BackgroundSerum eosinophil cationic protein (ECP) levels reflect ongoing eosinophilic airway inflammation and are used as a marker for asthma activity. ECP levels, however, may not be elevated in some asthmatic patients, even when they are symptomatic. ObjectiveTo clarify the characteristics of patients with ‘low’ ECP titres despite asthma exacerbation. MethodsSerum ECP levels were measured in 113 asthmatic patients during exacerbation. Patients were divided into two groups according to ECP titre: a high ECP group (H; ECP ≥ 16.0 µg/L) and a low ECP group (L; ECP <16.0 µg/L). Twenty-two patients who had recently received systemic steroids were excluded and the clinical features of the remaining patients in H (n = 54) and L (n = 37 were compared. ResultsGender, atopic or smoking status, disease severity, inhaled steroid or theophylline usage, peak expiratory flow (% personal best) and forced expiratory volume in 1 s (FEV1) (% predicted) did not significantly differ between the two groups. Patients in L were significantly older and had longer disease duration and lower serum IgE levels than those in H. Multivariate analysis combining age, disease duration and IgE levels showed that age and disease duration were independently associated with ECP level. Airway wall thickness, assessed in a subset of patients using computed tomography, was significantly larger in L. ConclusionSerum ECP levels in asthmatic patients may not be elevated during exacerbation and thus may not be a useful marker in patients who are older, have longer disease duration or possibly have thicker airway walls. Mechanisms other than eosinophilic inflammation, such as airway remodelling, may be involved in asthma exacerbation in these patients. [ABSTRACT FROM AUTHOR]

Background: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. Methods: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. Results: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme – the epithelial mesenchymal trophic unit – leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. Conclusions: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-βRs provide targets against which to develop novel therapies for chronic asthma.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The term ‘airway remodelling’ is now widely used to refer to the development of specific structural changes in the airway wall in asthma. Particular interest has focused on subepithelial fibrosis, myofibroblast accumulation, airway smooth muscle hyperplasia and hypertrophy, mucous gland and goblet cell hyperplasia, and epithelial disruption. The presence of these features is generally accepted, but further studies are still required to define the changes occurring more precisely at the pathological and ultrastructural levels. Attention also needs to be directed towards the existence of such changes in small airways. The natural history of the response has not been well described: remodelling is present in the airways of asthmatic children and of adults with newly diagnosed asthma, and studies that have attempted to relate the extent of remodelling to disease severity have produced conflicting findings. The role of remodelling in the progressive decline in lung function leading to fixed airflow obstruction seen in some patients is also unclear. Epidemiological studies are currently hindered by the absence of a useful non-invasive marker of remodelling. Airway remodelling is frequently assumed to be a consequence of chronic inflammation, but the precise relation between the remodelling and inflammatory components in asthma is unclear. The cellular and molecular events underlying the remodelling process are also poorly understood. There is therefore a need for the development and characterization of animal models that will allow these issues to be explored. Finally, the ability of currently available anti-asthma therapies to prevent or reverse airway remodelling is uncertain. There is some evidence that early treatment with inhaled corticosteroids can lead to improved outcome in asthma but this needs confirmation. Studies addressing the ability of corticosteroid treatment to reverse established structural changes have not produced consistent findings, and there is little information with regard to other therapies such as theophylline and antileukotriene agents. Effective treatment of airway remodelling may require the development of novel therapies directed against appropriate targets. [ABSTRACT FROM AUTHOR]

Asthma is a chronic heterogeneous respiratory condition that is mainly associated with sensitivity to airborne agents such as pollen, dust mite products and fungi. Key pathological features include increased airway inflammation and airway wall remodelling. In particular, goblet cell hyperplasia, combined with excess mucus secretion, impairs clearance of the inhaled foreign material. Furthermore, structural changes such as subepithelial fibrosis and increased smooth muscle hypertrophy collectively contribute to deteriorating airway function and possibility of exacerbations. Current pharmacological therapies focused on airway wall remodelling are limited, and as such, are an area of unmet clinical need. Sensitisation to the fungus, Aspergillus fumigatus, is associated with enhanced asthma severity, bronchiectasis, and hospitalisation. How Aspergillus fumigatus may drive airway structural changes is unclear, although recent evidence points to a central role of the airway epithelium. This review provides an overview of the airway pathology in patients with asthma and fungal sensitisation, summarises proposed airway epithelial cell–fungal interactions and discusses the initiation of a tissue remodelling response. Related findings from in vivo animal models are included given the limited analysis of airway pathology in patients. Lastly, an important role for Aspergillus fumigatus-derived proteases in triggering a cascade of damage-repair events through upregulation of airway epithelial-derived factors is proposed. [ABSTRACT FROM AUTHOR]

Background: Asthma is an airway disease characterized by airflow limitation and various additional clinical manifestations. Repeated inflammatory stimulation of the airways leads to epithelial-mesenchymal transition (EMT) which aggravates subepithelial fibrosis during the process of airway remodelling and enhances resistance to corticosteroids and bronchodilators in refractory asthma. There is growing evidence that IL-27 modulates airway remodelling, however, the molecular mechanisms involving IL-27 and EMT are poorly understood. The objective of this study was to investigate the effects of IL-27 on ovalbumin (OVA)-challenged asthmatic mice in vivo and TGF-β1-induced EMT in 16HBE cells in vitro., Methods: Airway inflammation, mucus secretion, and collagen deposition were analysed by conventional pathological techniques. The ratio of Th17 and Th9 cells in the spleen of mice was measured using flow cytometry, ELISA was performed for cytokine analysis to identify EMT-related molecules and signalling pathways, and other molecular and cellular techniques were used to explore the functional mechanism involving IL-27 and EMT., Results: Airway inflammation in asthmatic mice was significantly alleviated by IL-27, with downregulation of RhoA and ROCK, upregulation of E-cadherin, and a decrease of vimentin and α-SMA expression, compared to asthmatic mice. Moreover, the frequency of Th17 and Th9 cells in the spleen of asthmatic mice decreased following treatment with IL-27. In TGF-β1-induced 16HBE cells, the addition of IL-27 was shown to inhibit EMT, based on the expression of E-cadherin, vimentin, and α-SMA., Conclusion: Intranasal administration of IL-27 attenuates airway inflammation and EMT in a murine model of allergic asthma possibly by downregulating the RhoA/ROCK signalling pathway.

Background: Severe asthma with persistent airflow limitation (SA-PAL) and chronic obstructive pulmonary disease (COPD) are characterised by irreversible airflow limitation and the remodelling of the airways. The phenotypes of the diseases overlap and may cause diagnostic and therapeutic concerns. Methods: There were 10 patients with SA-PAL, 11 patients with COPD, and 10 healthy volunteers (HV) enrolled in this study. The patients were examined with a 128-multislice scanner at full inspiration. Measurements were taken from the third to ninth bronchial generations. Results: The thickness of the bronchial wall was greater in the SA-PAL than in the COPD group for most bronchial generations (p < 0.05). The mean lung density was the lowest in the SA-PAL group (−846 HU), followed by the COPD group (−836 HU), with no statistical difference between these two groups. The low-attenuation volume percentage (LAV% < −950 HU) was significantly higher in the SA-PAL group (15.8%) and COPD group (10.4%) compared with the HV group (7%) (p = 0.03). Conclusion: Severe asthma with persistent airflow limitation and COPD become similar with time within the functional and morphological dimensions. Emphysema qualities are present in COPD and in SA-PAL patients. [ABSTRACT FROM AUTHOR]