Neutrophil elastase

One intensively investigated feature of the inflammatory process in COPD is the release of proteases from neutrophils and monocytic cells that destroy elastin and other components of the interstitial matrix (Table 1). The best studied protease is neutrophil elastase. Independent of its elastolytic activity, neutrophil elastase is a potent secretagogue. More recently matrix metalloproteases (MMP) have received increasing attention, in particular MMP 12 (macrophages elastase). To which extent and how exactly these proteases become activated is not clear at present. 

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. 

PA S1 S01.131 Neutrophil elastase Drug target for emphysema, cystic fibrosis, adult respiratory distress syndrome, rheumatoid arthritis and other diseases... 

HNE Human neutrophil elastase HNG Human neutrophil gclatinase (MMP-9)... 

Wakselman, M. Joyeau, R. Kobaiter, R. Boggetto, N. Vergely, I. Maillard, J.-L. Okochi, V. Montagne, J.-J. Reboud-Ravaux, M. Functionahzed A-arylazetidinones as novel mechanism-based inhibitors of neutrophil elastase. FEBS Lett. 1991,282, 377-381. 

El Ouriaghli F, Fujiwara H, Melenhorst JJ, Sconocchia G, Hensel N, Barrett AJ. Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF implications for the regulation of granulopoiesis. Blood 2003 101(5) 1752-1758. 

IL-lra (17.5) Monocyte/macrophage, fibroblast Specifically inhibits IL-1 effects, including SIRS and sepsis in animal models and humans. Attenuation of coagulation, fibrinolytic, and complement systems, levels of PAF and neutrophil elastase. 

The family Droseraceae consists of four genera and about 100 species of perennial herbs, of which Drosera burmannii Vahl, Drosera rotundifolia L, Drosera indica L., and Drosera peltata Sm. are used in Asia for the treatment of cough. Naphthoquinones and flavonoids, which occur in this family, have not been fully studied for pharmacology, and it appears that flavonoids inhibit human neutrophil elastase, hence the potential for the treatment of inflammation. 

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. 

Pohl, J., Pereira, A., Martin, N. M., Spitznagel, J. K. (1990). Amino acid sequence of CAP37, a human neutrophil granule-derived antibacterial and monocyte-specific chemotactic glycoprotein structurally similar to neutrophil elastase. FEBS Lett. 272, 200-4. 

Ralfkiaer, E., Pulford, K. A. F., Lauritzen, A. F., Avnstrom, A., Guldhammer, B., and Mason, D. Y. (1989) Diagnosis of acute myeloid leukaemia with the use of monoclonal anti-neutrophil elastase (NP57) reactive with routinely processed biopsy samples. Histopathol. 14, 637-643. 

Gonzales, J. R., Hermann, J. M., Boedeker, R. H., Francz, P. L, Biesalski, H. K., and Meyle, J. (2001). Concentration of interleukin-1 p and neutrophil elastase activity in gingival crevi-cular fluid during experimental gingivitis. /. Clin. Periodontol. 28,544—549. 

Horwitz, M., Benson, K. F., Person, R. E., Aprikyan, A. G., and Dale, D. C., Mutations in ELA2, encoding neutrophil elastase define a 21-day biological clock in cyclic haematopoiesis. Nat. 

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... 

Role of ai-AT in the lungs In the normal lung, the alveoli are chronically exposed to low levels of neutrophil elastase released from activated and degenerating neutrophils. This proteolytic activity can destroy the elastin in alveolar walls if unopposed by the inhibitory action of a-rAT, the most important inhibitor of neu trophil elastase (see Figure 4.14). Because lung tissue cannot regenerate, emphysema results from the destruction of the con nective tissue of alveolar walls. 

Roberts, B., Markland, W., Ley, A., Kent, R., White, D., Guterman, S., and Ladner, R. (1992) Directed evolution of a protein selection of potent neutrophil elastase inhibitors displayed on M13 fusion phage Proc Natl Acad Sci USA 89, 2429-2433. 

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