Anna Kurdowska

Proteinase Inhibitors as Acute Phase Reactants: Regulation of Synthesis and Turnover

A dynamic equilibrium between the blood or tissue proteinases and their inhibitors is drastically disturbed during acute inflammation elicited by various noxious stimuli /Fritz, 1980; Koj 1985b; Fritz et al., 1986/. A massive release of proteolytic enzymes from injured cells and from infiltrating leucocytes and macrophages must be promptly neutralized by a range of antiproteases present in body fluids /Fig.1/. Since the reaction between proteinases and inhibitors is in most cases irreversible and resulting complexes are quickly removed the enhanced proteolytic activity could seriously deplete the body reserves of these antiproteases. As demonstrated by the elegant studies of Ohlsson / 1974 / and Fritz and co-workers /198O, 1986/ such situations occur in certain cases of acute pancreatitis and septic shock or endotoxaemia. Severe depletion of plasma level of proteinase inhibitors, and especially of α2-macroglobulin / α2M/, has a bad prognostic significance. However, the acute phase response usually facilitates replenishment of proteinase inhibitors due to their enhanced liver synthesis.

Comparison of the action of interleukin-6, phorbol myristate acetate, and glucagon on the acute phase protein production and amino acid uptake by cultured rat hepatocytes

Rat hepatocytes cultured in the medium containing dexamethasone and crude macrophage cytokines or recombinant IL-6 show not only an increased synthesis of acute phase proteins, but also an enhanced rate of uptake of the nonmetabolizable amino acid a-aminoisobutyric acid (AIB).’.’ Here, we demonstrate that phorbol myristate acetate (PMA), the known activator of kinase C, potentiates the action of IL-6, whereas glucagon selectively stimulates AIB uptake without affecting protein synthesis.

Multiple Functions of Neutrophil Proteinases and their Inhibitor Complexes

During inflammatory episodes neutrophils are recruited to the site of injury where they function as scavengers by killing bacteria and ingesting and degrading foreign and damaged human proteins. As a consequence of these processes significant quantities of neutrophil proteins are released extracellularly, both through cell leakage and cell death. This places a heavy burden on normal, healthy tissues which may now become susceptible to attack by neutrophil-derived oxidizing agents (myeloperoxidase-derived) and proteinases [primarily elastase (HNE) and cathepsin G (cat G)]. It is not clear as to how the body regulates the activity of myeloperoxidase, although it is likely that this involves the use of catalase in order to reduce H2O2 levels; however, to offset the possibility of protei-nase damage the body offers a series of inhibitors, primarily plasma derived, which function to specifically inactivate these enzymes. In particular, it is now known that human plasma α1 proteinase inhibitor (α1PI) regulates the activity of HNE while cat G is controlled by α1 antichymotrypsin (α1Achy).2

Comparison of antiproteolytic activities of alpha-1-proteinase inhibitors from the plasma of some mammalian species

Alpha-1-proteinase inhibitors isolated from plasmas of horse, ox, pig, rabbit and man were used for determination of some kinetic parameters of interaction with three horse leucocyte proteinases and bovine pancreatic trypsin and chymotrypsin. Effective molar ratio of enzyme-to-inhibitor, inactivation rate constant and inhibition constant were measured. In horse, ox, pig and rabbit two principal electrophoretic forms of alpha 1-PI could be distinguished. Both forms effectively inhibited trypsin but usually only one form reacted promptly and stoichiometrically with chymotrypsin and leucocyte elastases. It appears that genetic variability and functional heterogeneity of multiple forms of alpha 1-PI as well as lack of other tissue inhibitors of proteinases may be responsible for lung emphysema occurring in man and horse.