CIGARETTE-SMOKING, EMPHYSEMA, AND DAMAGE TO ALPHA(1)-PROTEINASE INHIBITOR

The proteinase-antiproteinase theory for the pathogenesis of emphysema proposes that the connective tissue destruction associated with emphy sema arises from excessive proteinase activity in the lower respirator y tract. For this reason, the relative activities of neutrophil elasta se and alpha(1)-proteinase inhibitor (alpha(1)-PI) are considered impo rtant. Most emphysema is observed in smokers; therefore, alpha(1)-PI h as been studied as a target for smoke-induced damage. Damage to alpha( 1)-PI in lung fluid could occur by several mechanisms involving specie s delivered to the lung by cigarette smoke and/or stimulated inflammat ory cells. Oxidative damage to alpha(1)-PI has received particular att ention, since both cigarette smoke and inflammatory cells are rich sou rces of oxidants. In this article we review almost two decades of rese arch on mechanistic studies of damage to alpha(1)-PI by cigarette smok e and phagocytic cells in vitro, studies emphasizing the importance of elastinolytic activity in the pathogenesis of emphysema in vivo and s tudies of human lung lavage fluid to detect defects in alpha(1)-PI at the molecular and functional levels.