Antitrypsins

Anti thymocyte globulin Antitrypsin Anti tuberculin agents Antitumor activity... 

Stavridi, E. S., O Malley, K., Lukacs, C. M., et al., 1996. Structural change in o -chymotrypsin induced by complexation widi o l-antitrypsin as. seen by enhanced. sen.sitivity to proteolysis. Biochemistry 35 10608-10615. 

These proteins are called acute phase proteins (or reactants) and include C-reactive protein (CRP, so-named because it reacts with the C polysaccharide of pneumococci), ai-antitrypsin, haptoglobin, aj-acid glycoprotein, and fibrinogen. The elevations of the levels of these proteins vary from as little as 50% to as much as 1000-fold in the case of CRP. Their levels are also usually elevated during chronic inflammatory states and in patients with cancer. These proteins are believed to play a role in the body s response to inflammation. For example, C-reactive protein can stimulate the classic complement pathway, and ai-antitrypsin can neutralize certain proteases released during the acute inflammatory state. CRP is used as a marker of tissue injury, infection, and inflammation, and there is considerable interest in its use as a predictor of certain types of cardiovascular conditions secondary to atherosclerosis. Interleukin-1 (IL-1), a polypeptide released from mononuclear phagocytic cells, is the principal—but not the sole—stimulator of the synthesis of the majority of acute phase reactants by hepatocytes. Additional molecules such as IL-6 are involved, and they as well as IL-1 appear to work at the level of gene transcription. 

Table 50-2 summarizes the functions of many of the plasma proteins. The remainder of the material in this chapter presents basic information regarding selected plasma proteins albumin, haptoglobin, transferrin, ceruloplasmin, aj-antitrypsin, aj i roglobulin, the immunoglobulins, and the complement system. The lipoproteins are discussed in Chapter 25. 

Deficiency of -Antiproteinase (tti-Antitrypsin) Is Associated With Emphysema One Type of Liver Disease... 

Deficiency of aj-antitrypsin is also implicated in one type of liver disease (a,-antitrypsin deficiency liver... 

Figure 50-6. Scheme illustrating (A) normal inactivation of elastase by a,-antitrypsin and (B) situation in which the amount of a,-antitrypsin is substantially reduced, resulting in proteolysis by elastase and leading to tissue damage. 

At present, severe ai-antitrypsin deficiency liver disease can be successfully treated by liver transplantation. In the future, introduction of the gene for normal ttj-antitrypsin into hepatocytes may become possible, but this would not stop production of the PiZ protein. Figure 50-7 is a scheme of the causation of this disease. 

Figure 50-7. Scheme of causation of a,-antitrypsin-deficiency iiver disease. The mutation shown causes formation of PiZZ (MiM 107400). (a,-AT, a,-antitrypsin.)... 

OCi-Antitrypsin is the major serine protease inhibitor of plasma, in particular inhibiting the elastase of neu-... 

Carrell RW, Lomas DA Alphai-antitrypsin deficiency—a model for conformational diseases. N Engl J Med 2002 346 45. 

Four naturally occurring thrombin inhibitors exist in normal plasma. The most important is antithrombin III (often called simply antithrombin), which contributes approximately 75% of the antithrombin activity. Antithrombin III can also inhibit the activities of factors IXa, Xa, XIa, Xlla, and Vila complexed with tissue factor. a2-Macroglobulin contributes most of the remainder of the antithrombin activity, with heparin cofactor II and aj-antitrypsin acting as minor inhibitors under physiologic conditions. 

There are a number of disorders, including cancer and shock, in which the concentrations of plasminogen activators increase. In addition, the antiplasmin activities contributed by tti-antitrypsin and a2-antiplas-min may be impaired in diseases such as cirrhosis. Since certain bacterial products, such as streptokinase, are capable of activating plasminogen, they may be responsible for the diffuse hemotthage sometimes observed in patients with disseminated bacterial infections. 

Courtney M., Jallat S., Tessier L-H., Benavente A., Crystal R.G. Lecocq J-P. (1985) Synthesis in E. coli of alpha,-antitrypsin variants of therapeutic potential for emphysema and thrombosis. Nature, 313, 149-151. 

---