Asthma and lower airway disease
The outer wall of small airways is a major site of remodeling in fatal asthma

https://doi.org/10.1016/j.jaci.2009.02.032Get rights and content

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.

Section snippets

Methods

This study was approved by the review board for human studies of the School of Medicine, São Paulo University.

Twenty-four patients who died of asthma and were autopsied between 1996 and 2003 were included in the study. All individuals had a previous history of asthma (information provided by a next of kin before autopsy). Further clinical data (smoking habits, treatment history, medical follow-up, and previous hospital admission caused by asthma) were obtained during a later interview with the

Results

The characteristics of the subjects are shown in Table II. The mean ages of asthmatic patients and control subjects were 40.9 and 48.7 years, respectively. Among the asthmatic patients, 7 were current smokers, and 1 was a former smoker. Only 9 asthmatic patients had a regular medical follow-up, and 9 patients had a previous hospital admission caused by asthma. All had been using inhaled β-agonists. Only 6 patients had been treated with corticosteroids: 1 had received beclomethasone regularly, 1

Discussion

In the present study we quantified structural (collagens I and III) and adhesive (fibronectin) ECM proteins, as well as MMPs and their inhibitors, in the large and small airways and alveolar parenchyma of subjects who had died of asthma and compared the results with those obtained from nonsmoking control subjects. The main finding of our study was the identification of the outer wall of small airways as the major site of airway remodeling in patients with fatal asthma, which presented

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    Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Laboratório de Investigação Médica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (LIM-05 HCFMUSP).

    Disclosure of potential conflict of interest: J. H. Lindeman has received research support from Abbott. The rest of the authors have declared that they have no conflict of interest.

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