Proteolytic Enzymes, their Inhibitors and Lung Diseases

The pathogenesis of many acute and chronic lung diseases remains a mystery. However, recent years have seen a rapidly increasing interest in the role of proteolytic enzymes and their inhibitors in modifying the inflammatory, destructive and reparative changes that occur in the lung. Much of this interest owes its existence to two observations in the early 1960s: firstly, the recognition that subjects with an inherited deficiency of α1-antitrypsin (α1-AT; the main serum inhibitor of proteolytic enzymes) had a high incidence of pulmonary emphysema [1], and secondly the demonstration by Gross et al. [2] that a proteolytic enzyme (papain) was capable of producing lesions similar to emphysema in experimental animals. These observations ultimately led to the proteinase—anti-proteinase theory of emphysema, which predicts that a state of balance occurs in the healthy lung in which the proteolytic enzyme inhibitors functionally equal or exceed the enzymes. Destructive lung disease occurs when the enzymes functionally exceed the inhibitors such that they remain active within the lung, resulting in digestion of connective tissue. This general concept of a disturbed proteinase—anti-proteinase balance within the lung has been recently applied to many other lung diseases, and some will be mentioned later. However, it is in the study of chronic bronchitis and emphysema that the concept has become most well established.