Controlled and uncontrolled asthma display distinct alveolar tissue matrix compositions

Abstract

ObjectiveWhether distal inflammation in asthmatics also leads to structural changes in the alveolar parenchyma remains poorly examined, especially in patients with uncontrolled asthma. We hypothesized that patients who do not respond to conventional inhaled corticosteroid therapy have a distinct tissue composition, not only in central, but also in distal lung.MethodsBronchial and transbronchial biopsies from healthy controls, patients with controlled atopic and patients with uncontrolled atopic asthma were processed for immunohistochemical analysis of fibroblasts and extracellular matrix molecules: collagen, versican, biglycan, decorin, fibronectin, EDA-fibronectin, matrix metalloproteinase (MMP)-9 and tissue-inhibitor of matrix metalloproteinase (TIMP)-3.ResultsIn central airways we found increased percentage areas of versican and decorin in patients with uncontrolled asthma compared to both healthy controls and patients with controlled asthma. Percentage area of biglycan was significantly higher in both central airways and alveolar parenchyma of patients with uncontrolled compared to controlled asthma. Ratios of MMP-9/TIMP-3 were decreased in both uncontrolled and controlled asthma compared to healthy controls. In the alveolar parenchyma, patients with uncontrolled asthma had increased percentage areas of collagen, versican and decorin compared to patients with controlled asthma. Patients with uncontrolled asthma had significantly higher numbers of myofibroblasts in both central airways and alveolar parenchyma compared to patients with controlled asthma.ConclusionsTissue composition differs, in both central and distal airways, between patients with uncontrolled and controlled asthma on equivalent doses of ICS. This altered structure and possible change in tissue elasticity may lead to abnormal mechanical properties, which could be a factor in the persistent symptoms for patients with uncontrolled asthma.

iNOS affects matrix production in distal lung fibroblasts from patients with mild asthma

“…Importantly, in our previous study where we investigated the effect of ICS (budesonide) on ECM production in bronchial fibroblasts from patients with asthma we could show that budesonide had almost none effect on ECM synthesis (51). We could also demonstrate that lung tissue composition differs between patients with controlled and uncontrolled asthma on equivalent doses of ICS, which support the impression that patients who have remaining symptoms despite conventional ICS therapy have a pronounced ECM remodelling in both central and distal airways (52). In another study with the glucocorticoidsteroid dexamethasone, ECM was decreased in fibroblasts from healthy control subjects but not from patients with asthma that was related to increased expression of activator protein-1 (AP-1) transcription factor in fibroblasts from patients with asthma.…”

Interplay of extracellular matrix and leukocytes in lung inflammation

“…Recent studies show that versican is expressed and accumulates in the lungs of mice in studies of gram-negative lung infection [59, 90], acute lung injury [93], allergen-induced airway inflammation [94], fibrosis [95], cancer [51, 55, 96, 97], and emphysema[98]. Similarly, in humans, versican accumulates in chronic lung diseases such as pulmonary fibrosis [99–101], acute respiratory distress syndrome [102, 103], asthma [104, 105], cancer [106], lymphangioleiomyomatosis [107], and chronic obstructive pulmonary disease (COPD) [108, 109]. Whereas numerous studies show that the re-expression and accumulation of versican is a common observation in lung disease, very little is known about the regulation of versican expression or the role of versican in the pathogenesis of lung disease.…”

“…In addition, increased accumulation of versican has been associated with both small and large airway remodeling seen in autopsy specimens following fatal asthma exacerbations [136]. Subjects with uncontrolled asthma demonstrate increased accumulation of versican in biopsy specimens from their central airways compared to healthy subjects with well controlled asthma [104]. Interestingly, these same subjects also demonstrated a greater number of myofibroblasts per unit area in tissue samples.…”

Uncontrolled asthmatics have increased FceRI+ and TGF‐β–positive MCTC mast cells and collagen VI in the alveolar parenchyma

“…An increasing body of evidence suggests that inflammatory processes in the distal airways contribute to asthma pathogenesis . For example, several studies have shown infiltration of leucocytes and fibroblasts in the alveolar parenchymal tissue . Inflammatory cells implicated in asthma, such as eosinophils, Th2 lymphocytes and mast cells, have also been shown to increase in distal airways compared to healthy controls …”

“…Although comprising a subpopulation of all asthmatics, this category has significantly lower quality of life and contributes considerably to the economic burden of asthma. We have previously shown that both central and distal proteoglycans and total collagen levels differ between patients with controlled and uncontrolled asthma, despite equivalent doses of ICS . Considering the proposed role for MCs in remodelling and the broad actions of collagens, the aim of this study was to investigate the composition of specific collagens along with MC phenotypes and their TGF‐β expression in patients with controlled and uncontrolled asthma.…”