Experimental studies on emphysema and chronic bronchial injury.

The discovery of the association of emphysema and homozygous alpha-1-proteinase inhibitor deficiency gave rise to the hypothesis that emphysema was caused by an imbalance between endogenous proteases and antiproteases. Experimental studies with enzymes have confirmed that emphysema is induced only by enzymes with elastolytic properties. The lesion produced is similar anatomically and physiologically to human emphysema. Genetic and nutritional models of emphysema that appear to be caused by elastic fiber degradation are also known. Alpha-1-protease inhibitor is normally present in the lung; alpha-2-macroglobulin which can loosely complex with elastases, may enter the injured lung and participate in its defense. Alpha-1-protease inhibitor may be inactivated by oxidants derived from cigarette smoke or endogenous phagocytes. The elastase/antielastase hypothesis of emphysema is also believed to be relevant in emphysema caused by cigarette smoking because cigarette smoke gives rise to increased numbers of neutrophils and macrophages in the lung thus increasing the elastase burden of the lung. The precise role of oxidation of alpha-1-protease inhibitor in-vivo by cigarette smoke is not yet clear. In-vitro and experimental data suggest that oxidants can also interfere with repair of lung matrix. A variety of injuries, including proteases, can give rise to secretory cell metaplasia in the central airways. Peripheral airways injury is produced by gases with oxidant properties such as ozone and NO2. The presence of a low molecular weight protease inhibitor in airway epithelial secretory cells when considered with enzyme-induced secretory cell metaplasia raises the possibility of a protease/antiprotease hypothesis of chronic bronchial injury. Although information on the pathogenesis of emphysema is still incomplete, efforts are being made to develop antiproteases which might be used in the prevention of emphysema and chronic bronchial injury.