Antiproteases

Alpha-l-antiprotease (ai-AP) limits tissue damage arising from the actions of the leucocyte protease, elastase (Carrell and Travis, 1985), and there is much evidence available for the oxidative inactivation of this protein by oxygen-derived free-radical species and hypochlorous acid/hypochlorite anion (HOCl/OCP). The mechanism of this inactivation appears to involve the oxidation of a critical methionine residue (Met-358) to its corresponding sulphoxide and methionine sulphoxide has been detected in ai-AP samples isolated from the lungs of cigarette smokers (Carp et al., 1982) and rheumatoid synovial fluids (Wong and Travis, 1980). 

Carp, H., Miller, F., Hoidal, J.R and Janoff, A. (1982). Potential mechanism of emphysema alpha-l-antiprotease inhibitor recovered from lungs of cigarette smokers contains oxidised methionine and has decreased elastase inhibitory capacity. Proc. Natl. Acad. Sci. USA 79, 2041-2046. 

Radicals in cigarette smoke have been implicated in inactivation of an antiprotease in the lungs which leads to the development of emphysema (HUS). 

The protective antiprotease -antitrypsin (AAT) inhibits several protease enzymes, including neutrophil elastase. In the presence of unopposed AAT activity, elastase attacks elastin, which is a major component of alveolar walls. A hereditary deficiency of AAT results in an increased risk for premature development of emphysema. In the inherited disease, there is an absolute deficiency of AAT. In emphysema resulting from cigarettesmoking, the imbalance is associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several other proteases, including cathepsins and metalloproteinases. In addition, oxidative stress reduces antiprotease (or protective) activity. 

A sophisticated respiratory host defence system has evolved to clear airborne particles and potential pathogens in inspired air [106, 143], The system comprises mechanical (i.e. air filtration, cough, sneezing and mucociliary clearance), chemical (antioxidants, antiproteases and surfactant lipids) and immunological defence mechanisms and is tightly regulated to minimise inflammatory reactions [92, 143],... 

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

Not all enzyme exposed workers develop byssinosis, however, suggesting that certain individuals are hypersusceptible. It is possible that antiproteases such as serum alpha anti-trypsin (SAT) may play a role. SAT is an antiprotease capable of... 

Leqpeptln-acld reductase is Inhibited by leupeptin, but not by elastatlnal (42). This specific inhibition indicates that leppeptln acid which has no antiprotease activity is produced within cells on the other h uld, the letq>eptin prodviced from leupeptin acid is not accvimulated in cells, but is rapidly released extracellularly. 

A high fatality rate associated with this disease suggests that the effectiveness of conservative and surgical treatment is not sufficient in the case of acute pancreatitis. New methods of extracorporeal detoxification using hemoperfusion over carbon sorbents has made it possible to improve the outcome of pancreatitis treatment. However, hemosorption leads to only a transient decrease in blood proteolytic activity and does not correct the imbalance in the protease-inhibitor system, and the carbon hemosorbents are nonspecific. The development and application of antiprotease hemosorbents with specific bioligands therefore has potential in pancreatitis treatment. 

The present stndy shows effectiveness of the biospecific antiprotease hemosor-bent Ovosorb in the treatment of critically ill patients with destrnctive pancreatitis. Effectiveness of Ovosorb is mediated mostly via redaction of endogenous intoxication, fnnctional and metabolic disorders. 

N.A. Ribes nigrum L. Anthocyanosides, antiprotease, tannins, vitamins , B2, , P, citric acid, pectin.102 Diuretic and diaphoretic properties, urinary infection, rheumatism and diarrhea. 

L7. Larvin, M., Wilson, C., and Heath, D., A prospective, multicenter, randomized trial of intraperi-toneal antiprotease therapy for acute pancreatitis. Gastroenterology 112,274A (1992). 

Ul. Uhl, W., and Biichler, M., PMN-elastase in comparison with CRP, antiproteases, and LDH as indicators of necrosis in human acute pancreatitis. Pancreas 6, 253 (1991). 

W7. Wilson, C., C-reactive protein, antiproteases and complement factors as objective markers of severity in acute pancreatitis. Br. J. Surg. 76, 177 (1989). 

TFPI, when administered to rabbits, has been shown to have an antithrombotic effect when thromboplastin was used as a thrombogenic challenge (I 10). TFPI was also shown to be an effective inhibitor when thrombosis was induced in rabbit jugular veins by endothelial destruction and restricted blood flow. The antithrombotic and antiprotease actions of TFPI have been tested in several other animal models. Warn-Cramer et al. investigated the effect of immunodepletion of TFPI in factor Vila and Xa induced coagulation in rabbits (III). These rabbits were observed to be sensitized to the procoagulant effects of factor Vila, but not factor Xa in the absence of factor Vila. Two studies have indicated that TFPI administration reduces the lethal effects of . coli administration in a septic shock model in baboons (I 12). These studies also indicated that TFPI may have an anti-inflammatory effect, as an attenuation of the IL-6 response was also observed. Administration of TFPI has been observed to prevent... 

These last reactions are considered the cause of the reperfusion damage (7-9). Both reactions need 02to be completed. Since during ischemia the availability of 02 is extremely low, the tendency is to accumulate hypoxantine, locally When suddenly the 02 becomes available a massive OS is developed. Unfortunately, the antiproteases (anticoagulant enzymes) are much more sensitive to the oxidation than proteases (10,1 I) such as thrombin, and the consequence is the formation of a thrombus. OS facilitates the precipitation of acute ischemic episodes and antioxidants may limit the damage/incidence of an acute episode (165,167,168) for the prevention of acute episodes. 

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. 

Other conversions to unnatural residues occur when most proteins are exposed to high pH (80, 81,82). The high pH causes a -elimination of a cystine (see Figure 16) or O-substituted serine or threonine, with the formation of a dehydroalanine or a dehydro-a-aminobutyrate. Such products are subject to nucleophilic attack by the e-amino group of a lysine to form a cross-linkage, such as lysinoalanine, or attack by cysteine to form lanthionine. Walsh et al. (81) have taken advantage of the formation of these cross-links to produce avian ovomucoids that have nonreducible cross-links and have lost the antiprotease activity of one of their two inhibitory sites (see Figure 17). 

---