Protease-antiprotease

A. Janoff, Elastases and Emphysema. Current Assessment of the Protease-Antiprotease Hypothesis , Am. Rev. Respir. Dis. 1985, 132, 417-433. 

Blood clotting is a delicately balanced phenomenon involving proteases, antiproteases, and protease substrates. Generally speaking, each forward action engenders some backward-inclined response. Various metaphors can be applied to its step-by-step evolution action-reaction, point and counterpoint, or good news and bad news. My favorite, however is yin and yang. 

Pancreatitis. In severe attacks of acute pancreatitis, plasma levels of antithrombin III and AMG may be markedly depressed other inhibitors are normal or increased, and protease-antiprotease complexes are increased. In the peritoneal fluid, all major protease inhibitors are decreased or absent. 

It should be pointed out that while the protease-antiprotease theory of emphysema is currently the dominant hypothesis used to explain the etiology of emphysema, other factors must also be considered as contributing to the development of this disease. For example, oxidants, present in smoke, probably contribute in other fashions besides inactivating a -Pl. Such substances are capable of oxidizing a variety of cellular components (lipids, enzymes, and nucleic acids) and in this way may destroy parts of the alveolar epithelium, thus facilitating the exposure of elastin fragments present in the interstitial space to elastase. 

A50. Janoff, A. Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis Am. Rev. 27A67. 

Stockley RA. Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 1999 160 849-852. 

Birrer P, McElvaney NG, Rudeberg A, Sommer CW, Liechti-Gallati S, Kraemer R, Hubbard R, Crystal RG. Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med 1994 150 207. 

The ascorbic acid-vitamin E interaction is also important to maintain the protease-antiprotease balance in the lung. Ascorbic acid reacts with glutathione, and through antioxidant synergism it can increase the effectiveness of vitamin E. The following series of enzymatic reduction reactions that occur in the cells illustrates the participation of ascorbic acid in the inhibition of lipid peroxidation. 

Another important neutrophil function that can influence the protease-antiprotease balance is the generation of hypochlorous acid (HOCl) and N-chloramines via the myeloperoxidase-H202-halide system. HOCl and N-chloramines efficiently oxidize or chlorinate a wide number of molecules including both a2-macroglobulin and a 1-antiprotease (43,44). Up to 2500 to 5000 nmol of HOCl can be generated by as few as 25 x 106 neutrophils (45). Furthermore, the ability of HOCl and N-chloramines to activate latent MMPs may shift the protease-anti-protease equilibrium further towards degradation (46,47). 

Janoff A (1985) Elastases and emphysema current assessment of the protease-antiprotease hypothesis. Am Rev Respir Dis 132 417-433... 

Motta, J.P., Magne, L., Descamps, D., et al. (2011) Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis. Gastroenterology 140, 1272—1282. 

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