Disruption of the lung structure maintenance programme: a comprehensive view of emphysema development

Abstract

The lung is highly exposed to the external environment and must cope with a number of challenges from inhaled particles, toxic gases and invading microorganisms. Defence against these external injuries depends on various mechanisms (antioxidants, antiproteases and the immune response), and an efficient system for removing and replacing apoptotic cells. Failure to cope with external injury may lead to lung damage and destruction. Emphysema is a characteristic feature in the lungs of patients with chronic obstructive pulmonary disease (COPD). Its pathogenesis is far from being completely understood. More than 40 yrs ago, investigators reported that the instillation of proteolytic enzymes in rats caused airspace enlargement 1 and that genetic deficiency in the neutrophil elastase inhibitor α1-antitripsin was also associated with emphysema 2. These observations led to the hypothesis that emphysema was the result of an imbalance between proteolytic and antiproteolytic agents. The subsequent demonstration of increased numbers of neutrophils and macrophages in the lungs of smokers, and the known capacity of these cells to produce proteolytic enzymes, pointed to a connection between the inflammatory reaction characteristic of COPD and proteolytic/antiproteolytic imbalance, leading to the prevalent theory of an inflammatory–proteolytic origin of lung destruction in COPD. This theory does not, however, explain all the features in the lung of patients with COPD 3. In recent years, alternative or complementary hypotheses have been proposed, including oxidative stress 4, apoptosis 5, cell senescence 6 and autoimmunity 7, providing a more complex and comprehensive view of the pathogenesis of emphysema in COPD. Central to our current understanding of the pathogenesis of emphysema is the concept of a lung structure maintenance programme 8, 9, which considers that the lung is a metabolically active organ designed for gas exchange and the processing of endogenous substances constantly exposed …