IngentaConnect Pathogenesis of COPD. Part I. The role of protease-antiprotease i...

Abstract:

This review covers protease-antiprotease imbalance in the development of emphysema in smokers. This imbalance is likely to play a major pathogenic role in the development of emphysema in subjects with severe α₁-antitrypsin deficiency who smoke because of a deficient antiprotease protection against neutrophil elastase release in the lung. Neutrophil elastase is a potent elastolytic enzyme, and its instillation in the lungs of animals results in emphysema. Smoking attracts neutrophils to the lungs and there is an additional accumulation of neutrophils, because the abnormal antitrypsin polymerizes in the lungs and acts as a chemo-attractant to neutrophils.

In subjects who do not have antitrypsin deficiency, the case for elastolytic injury by neutrophils causing emphysema is less definite, because of the lack of a severe deficiency of active α₁-ntitrypsin leading to unopposed elastolysis by neutrophil elastase. It is likely that alveolar macrophages play a pathogenic role in emphysema; they express potent elastolytic enzymes, cathepsins and matrix metalloproteases (MMPs), which are induced by smoking. The numbers of macrophages are increased in the region of the respiratory bronchiole, where centrilobular emphysema develops in smokers. Macrophage cathepsins are inhibited by an antiprotease cystatin C, while the MMPs are inhibited by the tissue inhibitors of metalloproteases (TIMPs).

Some pro-inflammatory mediators induce release of MMPs from macrophages without inducing increase in TIMPs, leading to possible protease-antiprotease imbalance. Studies of proteases in alveolar macrophages obtained by bronchoalveolar lavage and studies on lung tissue indicate increased protease expression in subjects with chronic obstructive pulmonary disease (COPD) compared to subjects without COPD.

Keywords: emphysema; protease-antiprotease imbalance; neutrophil elastase; matrix metalloproteases; smoking

Document Type: Invited paper

Affiliations: 1: Division of Respiratory Medicine, Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada 2: University of British Columbia Respiratory Division, Vancouver, British Columbia, Canada

Pathogenesis of COPD. Part I. The role of protease-antiprotease imbalance in emphysema [State of the Art Series. Chronic obstructive pulmonary disease in high- and low-income countries. Edited by G. Marks and M. Chan-Yeung. Number 3 in the series]