The outer wall of small airways is a major site of remodeling in fatal asthma

Background

Structural and inflammatory changes in asthma involve both the large and small airways, with involvement of the distal lung being related to disease severity. We have previously shown that changes in the extracellular matrix (ECM) composition of the distal lung are associated with loss of alveolar attachments in patients with fatal asthma. However, major ECM elements, such as collagen I and fibronectin and their regulators, have not been addressed at the distal level.

Objective

We sought to evaluate ECM remodeling in the distal lungs of asthmatic patients.

Methods

Using immunohistochemistry and image analysis, we determined the content of collagen I and III, fibronectin, and matrix metalloproteinases (MMPs) 1, 2, and 9 and tissue inhibitors of metalloproteinase (TIMPs) 1 and 2 in the large and small airways and lung parenchyma of 24 patients with fatal asthma and compared the results with those of 11 nonasthmatic control subjects. Protein content was defined as the area of positive staining divided by basement membrane or septum length.

Results

We observed increased collagen I and decreased collagen III content in the small airways of asthmatic patients compared with that seen in control subjects. Greater fibronectin and MMP-1, MMP-2, and MMP-9 content was observed at the outer area of the small airways in asthmatic patients. MMP content was also increased in the peribronchiolar parenchyma in asthmatic patients. In contrast, TIMP expression was only increased in the large airways of asthmatic patients compared with that seen in control subjects.

Conclusions

The outer area of the small airways is a major site of ECM remodeling in fatal asthma, potentially contributing to functional changes and the loss of airway-parenchyma interdependence observed in patients with fatal asthma.

Key words: Collagen, fatal asthma, extracellular matrix, distal lung, remodeling

Abbreviations used: BM, Basement membrane, ECM, Extracellular matrix, IA, Inner area, MMP, Matrix metalloproteinase, OA, Outer area, Pi, Basement membrane perimeter, PP, Peribronchiolar parenchyma, SM, Smooth muscle, TIMP, Tissue inhibitor of metalloproteinase