Destruction of connective tissue by leukocyte elastase is the major pathogenetic event in the development of pulmonary emphysema. In the normal lung alpha 1-proteinase inhibitor (alpha1PI) and a bronchial mucus inhibitor are present in sufficient amounts to effectively inhibit the elastase released from PMN leukocytes during phagocytosis. Smoking promotes the development of emphysema by upsetting this enzyme/inhibitor balance in at least 4 different ways: 1) The macrophage and PMN leukocyte accumulation in the lung and consequently the proteinase load is increased; 2) the alpha1PI in the lung may become inactivated proteolytically, e.g. by cathepsin B; 3) the alpha1PI as well as the bronchial mucus inhibitor can be inactivated by oxidation through "smoke oxidants" directly, or 4) through the myeloperoxidase system. Analysis of bronchioalveolar lavage fluids confirms that all of these mechanisms do in fact occur, but suggests at the same time that the increased enzyme load to the lung may be the most important factor in the genesis of emphysema in smokers.