Neutrophils proteinases

B30. De Boer, J. R, Creasey, A. A., Chang, A., Abbink, J. J., Roem, D., Eerenberg, A. J., Hack, C. E., and Taylor, F. B., Alpha-2 macroglobulin functions as an inhibitor of fibrinolytic, clotting and neutrophilic proteinases in sepsis Studies using a baboon model. Infect. Immun. 61,5035-5043 (1993). 

In adults, a severe form of lung injury can develop in association with sepsis, pneumonia, and injury to the lungs due to trauma or surgery. This catastrophic disorder is known as acute respiratory distress syndrome (ARDS) and has a mortality rate of more than 40%. In ARDS, one of the major problems is a massive influx of activated neurophils which damage both vascular endothelium and alveolar epithelium and result in massive pulmonary edema and impairment of surfactant function. Neutrophil proteinases (e.g., elastase) break down surfactant proteins. A potential therapeutic strategy in ARDS involves administration of both surfactant and antiproteinases (e.g., recombinant a I -antitrypsin). 

There is no question about the destructive potential of neutrophil proteinases and their ability to degrade extracellular matrices. A topic that has been more... 

M. Bergenfeldt, L. Axelsson, and K. Ohlsson. Release of neutrophil proteinase 4(3) and leukocyte elastase during phagocytosis and their interaction with proteinase inhibitors. Scand. J. Clin. Invest. 52 823 (1992). 

Smith, C. E. Stack, M. S. Johnson, D. A. Ozone effects on inhibitors of human neutrophil proteinases. Arch. Biochem. Biophys., 1987,253,146-155. 

Lundgren JD, Rieves RD, Mullol J, Logun C, Shelhamer JH. The effect of neutrophil proteinase enzymes on the release of mucus iiom feline and human airway... 

Elastase-like proteinases are serine proteinases that recognized peptide residues with linear aliphatic side chains (alanyl, valyl, leucyl or isoleucyl residues) and that effect hydrolysis of the polypeptide chain on the carboxy-terminal side of these residues. Examples of elastase-like proteinase are pancreatic elastase, neutrophil elastase and proteinase-3. 

The expression of many of these molecules has been studied during various stages of differentiation of normal neutrophils and also of corresponding leukemic cells employing molecular biology techniques (eg, measurements of their specific mRNAs). For the majority, cDNAs have been isolated and sequenced, amino acid sequences deduced, genes have been localized to specific chromosomal locations, and exons and intron sequences have been defined. Some important proteinases of neutrophils are listed in Table 52-12. 

The Proteinases of Neutrophils Can Cause Serious Tissue Damage If Their Actions Are Not Checked... 

Table 52-12. Proteinases of neutrophils and antiproteinases of plasma and tissues. ...

The proteinases of neutrophils can digest many tissue proteins normally, this is kept in check by a battery of antiproteinases. However, this defense mechanism can be overcome in certain circumstances, resulting in extensive tissue damage. 

Desrochers, P.E. and Weiss, S.J. (1988). Proteolytic inactivation of alpha-l-proteinase inhibitor by a neutrophil metalloproteinase. J. Clin. Invest. 81, 1646-1650. 

Inflammatory injury is tied to both neutrophil release of neutral proteinases and a respiratory burst with production of superoxide anion and hydrogen peroxide... 

Eosinophils may be increased in some patients, particularly during exacerbations. Activated inflammatory cells release a variety of mediators, most notably leukotriene B4, interleukin-8, and tumor necrosis factor-a (TNF-a). Various proteinases, such as elastase, cathepsin G, and proteinase-3, are secreted by activated neutrophils. These mediators and proteinases are capable of sustaining inflammation and damaging lung structures. 

C5a is inactivated by the myeloperoxidase-H202 system, which oxidises a methionine residue (Met 70) on the molecule group A streptococcal endo-proteinases also abolish chemotactic activity of C5a and related compounds. Neutrophil lysosomal enzymes (e.g. elastase and cathepsin G) also destroy C5a chemotactic activity, but as these proteases are inhibited by the serum antiproteinases, a -antiproteinase and a2-macroglobulin, the physiological role of neutrophilic proteases in the inactivation of C5a is questionable. Two chemotactic factor inactivators have been found in human serum an a-globulin that specifically and irreversibly inactivates C5-derived chemotactic factors, and a / -globulin that inactivates bacterial chemotactic factors. These activities are heat labile (destroyed by treatment at 56 °C for 30 min) and are distinct from those attributable to anaphylatoxin inactivator. An apparently specific inhibitor of C5-derived chemotactic activity has also been described in human synovial fluid and peritoneal fluid. This factor (molecular mass of 40 kDa) is heat stable and acts directly on C5a. 

Clinical pharmacology Alpha-1 antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alphai-proteinase inhibitor is associated with slowly progressive, severe, panacinar emphysema that most often manifests itself in the third to fourth decades of fife. The pathogenesis of development of emphysema in alpha-1 antitrypsin deficiency is believed to be due to a chronic biochemical imbalance between elastase and alphai-proteinase inhibitor (the principal inhibitor of neutrophil elastase), which is deficient in alpha-1 antitrypsin disease. As a result it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic low-level burden of neutrophils in the lower respiratory tract, resulting in progressive degradation... 

Pinter, M., and Friedrich, P., 1988, The calcium dependent proteolytic system calpain-calpatatin in Drosophila melanogaster, Biochem J., 253, 467-473 Pinter, M., Stierandova, A., and Friedrich, P., 1992, Purification and characterization o a Ca2 activated thiol protease from drosophila melanogaster, Biochemistry, 31, 8201-8206 Pontremoli, S., Melloni, E., Michetti, M., Salamino, F., Sparatore, B., Horecker, B., 1988, An endogenous activator of the Ca2+ -dependent proteinase of human neutrophils that increases its affinity for Ca2+, Proc. Natl. Acad. Sci., USA, 85, 1740-1743... 

Wright, C.D., J.A. Kennedy, R.J. Zitnik, and M.A. Kashem. 1999. Inhibition of murine neutrophil serine proteinases by human and murine secretory leukocyte protease inhibitor. Biochem. Biophys. Res. Commun. 254 614—617. 

Human neutrophil elastase is the proteinase that has received by for the most attention over the last 30 years primarily due to the foci that it was thought to be the rntyor factor involved in the development of emphysema. This assumption was derived from the observation of Eriksson In 1963 that individuals with an inherited deficiency of cti-PI developed emphysema at an early age [11]. One year later. Gross showed that emphysema could be produced in experimental animals after intratracheal administration of papain, a plant proteinase with a... 

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