PROTEINASE INHIBITORS | Cystatins

Pemberton, P.A.

The cystatins comprise a superfamily of proteins related primarily by virtue of DNA and amino acid sequence homology. The superfamily consists so far of four distinct types of molecules ranging from the simpler low-molecular-weight type I and II cystatins, which function primarily to inhibit lysosomal cysteine proteinases (CPs), to the higher-molecular-weight type III and IV cystatins, which possess additional latent functions expressed only during episodes of injury and inflammation, or have evolved entirely novel inhibitory functions. The role cystatins play in respiratory diseases such as asthma and COPD is poorly understood. However, they do modulate the immune response by acting directly on neutrophils, macrophages, and antigen presenting cells. It is also clear that they do not function independently of other proteolytic pathways involved in remodeling of the lung. Limited proteolysis inactivates cystatins allowing lysosomal CP activity to directly contribute to lung tissue degradation and also liberates kinins which signal through G-protein-coupled receptors to cause both constriction and dilation of the bronchioles, pain via stimulation of sensory nerves, mucus secretion, cough, and edema.