Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1993 Apr;108(4):1100–1106. doi: 10.1111/j.1476-5381.1993.tb13511.x

Inhibition by recombinant SLPI and half-SLPI (Asn55-Ala107) of elastase and cathepsin G activities: consequence for neutrophil-platelet cooperation.

P Renesto 1, V Balloy 1, T Kamimura 1, K Masuda 1, A Imaizumi 1, M Chignard 1
PMCID: PMC1908137  PMID: 8097952

Abstract

1. The capacity of recombinant human secretory leukocyte proteinase inhibitor (SLPI) to inhibit human leukocyte elastase (HLE) and cathepsin G (Cat G) was investigated and compared with a recombinant truncated form (carboxyl-terminal domain, Asn55-Ala107) called 1/2 SLPI. 2. Both compounds were efficient when tested against enzymatic activities of purified HLE and Cat G indicating that the HLE- and Cat G-inhibitory sites were preserved in the truncated form. SLPI and 1/2 SLPI also affected platelet activation induced by 0.2 microM Cat G (IC50 = 112 +/- 13 nM for SLPI and 280 +/- 12 nM for 1/2 SLPI). 3. The effects of SLPI and 1/2 SLPI were then tested against polymorphonuclear neutrophil (PMN)-mediated platelet activation, a cell-to-cell interaction mediated by HLE and Cat G released from PMN. In this experimental system, addition of SLPI or 1/2 SLPI before N-formyl-Met-Leu-Phe (fMLP) led to the inhibition of the resulting platelet activation. As was the case for Cat G enzymatic activity and Cat G-induced platelet activation, SLPI was more efficient than 1/2 SLPI (IC50 = 676 +/- 69 nM vs 1121 +/- 150 nM). 4. The ratio of the IC50 against PMN-mediated platelet activation compared to purified Cat G-mediated platelet activation was 6.03 for SLPI and 4.32 for 1/2 SLPI. This difference may be due to the smaller size of the truncated form which could allow this molecule to diffuse more easily between PMN and platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
1100

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baugh R. J., Travis J. Human leukocyte granule elastase: rapid isolation and characterization. Biochemistry. 1976 Feb 24;15(4):836–841. doi: 10.1021/bi00649a017. [DOI] [PubMed] [Google Scholar]
  2. Beatty K., Bieth J., Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem. 1980 May 10;255(9):3931–3934. [PubMed] [Google Scholar]
  3. Boudier C., Bieth J. G. Mucus proteinase inhibitor: a fast-acting inhibitor of leucocyte elastase. Biochim Biophys Acta. 1989 Mar 16;995(1):36–41. doi: 10.1016/0167-4838(89)90230-6. [DOI] [PubMed] [Google Scholar]
  4. Boudier C., Bieth J. G. The proteinase: mucus proteinase inhibitor binding stoichiometry. J Biol Chem. 1992 Mar 5;267(7):4370–4375. [PubMed] [Google Scholar]
  5. Boudier C., Holle C., Bieth J. G. Stimulation of the elastolytic activity of leukocyte elastase by leukocyte cathepsin G. J Biol Chem. 1981 Oct 25;256(20):10256–10258. [PubMed] [Google Scholar]
  6. Braun N. J., Schnebli H. P. A brief review of the biochemistry and pharmacology of Eglin c, an elastase inhibitor. Eur J Respir Dis Suppl. 1986;146:541–547. [PubMed] [Google Scholar]
  7. Chignard M., Selak M. A., Smith J. B. Direct evidence for the existence of a neutrophil-derived platelet activator (neutrophilin). Proc Natl Acad Sci U S A. 1986 Nov;83(22):8609–8613. doi: 10.1073/pnas.83.22.8609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Crystal R. G., Brantly M. L., Hubbard R. C., Curiel D. T., States D. J., Holmes M. D. The alpha 1-antitrypsin gene and its mutations. Clinical consequences and strategies for therapy. Chest. 1989 Jan;95(1):196–208. doi: 10.1378/chest.95.1.196. [DOI] [PubMed] [Google Scholar]
  9. Del Maschio A., Evangelista V., Rajtar G., Chen Z. M., Cerletti C., De Gaetano G. Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents. Am J Physiol. 1990 Mar;258(3 Pt 2):H870–H879. doi: 10.1152/ajpheart.1990.258.3.H870. [DOI] [PubMed] [Google Scholar]
  10. Eisenberg S. P., Hale K. K., Heimdal P., Thompson R. C. Location of the protease-inhibitory region of secretory leukocyte protease inhibitor. J Biol Chem. 1990 May 15;265(14):7976–7981. [PubMed] [Google Scholar]
  11. Erikson S. Proteases and protease inhibitors in chronic obstructive lung disease. Acta Med Scand. 1978;203(6):449–455. [PubMed] [Google Scholar]
  12. Ferrer-Lopez P., Renesto P., Schattner M., Bassot S., Laurent P., Chignard M. Activation of human platelets by C5a-stimulated neutrophils: a role for cathepsin G. Am J Physiol. 1990 Jun;258(6 Pt 1):C1100–C1107. doi: 10.1152/ajpcell.1990.258.6.C1100. [DOI] [PubMed] [Google Scholar]
  13. Gervaix A., Thompson R., Bieth J. G., Nick H. P., Suter S. Secretory leucocyte proteinase inhibitor: inhibition of fibronectin degradation by neutrophil elastase. Eur Respir J. 1992 May;5(5):566–575. [PubMed] [Google Scholar]
  14. Heffner J. E., Sahn S. A., Repine J. E. The role of platelets in the adult respiratory distress syndrome. Culprits or bystanders? Am Rev Respir Dis. 1987 Feb;135(2):482–492. doi: 10.1164/arrd.1987.135.2.482. [DOI] [PubMed] [Google Scholar]
  15. Henson P. M., Johnston R. B., Jr Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest. 1987 Mar;79(3):669–674. doi: 10.1172/JCI112869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hubbard R. C., McElvaney N. G., Sellers S. E., Healy J. T., Czerski D. B., Crystal R. G. Recombinant DNA-produced alpha 1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with alpha 1-antitrypsin deficiency. J Clin Invest. 1989 Oct;84(4):1349–1354. doi: 10.1172/JCI114305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Janoff A. Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis. Am Rev Respir Dis. 1985 Aug;132(2):417–433. doi: 10.1164/arrd.1985.132.2.417. [DOI] [PubMed] [Google Scholar]
  18. Janoff A., Sloan B., Weinbaum G., Damiano V., Sandhaus R. A., Elias J., Kimbel P. Experimental emphysema induced with purified human neutrophil elastase: tissue localization of the instilled protease. Am Rev Respir Dis. 1977 Mar;115(3):461–478. doi: 10.1164/arrd.1977.115.3.461. [DOI] [PubMed] [Google Scholar]
  19. Janusz M. J., Doherty N. S. Degradation of cartilage matrix proteoglycan by human neutrophils involves both elastase and cathepsin G. J Immunol. 1991 Jun 1;146(11):3922–3928. [PubMed] [Google Scholar]
  20. Lucey E. C., Stone P. J., Ciccolella D. E., Breuer R., Christensen T. G., Thompson R. C., Snider G. L. Recombinant human secretory leukocyte-protease inhibitor: in vitro properties, and amelioration of human neutrophil elastase-induced emphysema and secretory cell metaplasia in the hamster. J Lab Clin Med. 1990 Feb;115(2):224–232. [PubMed] [Google Scholar]
  21. Martodam R. R., Baugh R. J., Twumasi D. Y., Liener I. E. A rapid procedure for the large scale purification of elastase and cathepsin G from human sputum. Prep Biochem. 1979;9(1):15–31. doi: 10.1080/00327487908061669. [DOI] [PubMed] [Google Scholar]
  22. Merritt T. A., Cochrane C. G., Holcomb K., Bohl B., Hallman M., Strayer D., Edwards D. K., 3rd, Gluck L. Elastase and alpha 1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome. Role of inflammation in the pathogenesis of bronchopulmonary dysplasia. J Clin Invest. 1983 Aug;72(2):656–666. doi: 10.1172/JCI111015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mooren H. W., Kramps J. A., Franken C., Meijer C. J., Dijkman J. A. Localisation of a low-molecular-weight bronchial protease inhibitor in the peripheral human lung. Thorax. 1983 Mar;38(3):180–183. doi: 10.1136/thx.38.3.180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nakajima K., Powers J. C., Ashe B. M., Zimmerman M. Mapping the extended substrate binding site of cathepsin G and human leukocyte elastase. Studies with peptide substrates related to the alpha 1-protease inhibitor reactive site. J Biol Chem. 1979 May 25;254(10):4027–4032. [PubMed] [Google Scholar]
  25. Puchelle E., Hinnrasky J., Tournier J. M., Adnet J. J. Ultrastructural localization of bronchial inhibitor in human airways using protein A-gold technique. Biol Cell. 1985;55(1-2):151–154. doi: 10.1111/j.1768-322x.1985.tb00418.x. [DOI] [PubMed] [Google Scholar]
  26. Renesto P., Ferrer-Lopez P., Chignard M. Interference of recombinant eglin C, a proteinase inhibitor extracted from leeches, with neutrophil-mediated platelet activation. Lab Invest. 1990 Apr;62(4):409–416. [PubMed] [Google Scholar]
  27. Rice W. G., Weiss S. J. Regulation of proteolysis at the neutrophil-substrate interface by secretory leukoprotease inhibitor. Science. 1990 Jul 13;249(4965):178–181. doi: 10.1126/science.2371565. [DOI] [PubMed] [Google Scholar]
  28. Saklatvala J., Barrett A. J. Identification of proteinases in rheumatoid synovium. Detection of leukocyte elastase cathepsin G and another serine proteinase. Biochim Biophys Acta. 1980 Sep 9;615(1):167–177. doi: 10.1016/0005-2744(80)90020-0. [DOI] [PubMed] [Google Scholar]
  29. Selak M. A., Chignard M., Smith J. B. Cathepsin G is a strong platelet agonist released by neutrophils. Biochem J. 1988 Apr 1;251(1):293–299. doi: 10.1042/bj2510293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Selak M. A., Smith J. B. Cathepsin G binding to human platelets. Evidence for a specific receptor. Biochem J. 1990 Feb 15;266(1):55–62. doi: 10.1042/bj2660055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Senior R. M., Tegner H., Kuhn C., Ohlsson K., Starcher B. C., Pierce J. A. The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis. 1977 Sep;116(3):469–475. doi: 10.1164/arrd.1977.116.3.469. [DOI] [PubMed] [Google Scholar]
  32. Smith C. E., Johnson D. A. Human bronchial leucocyte proteinase inhibitor. Rapid isolation and kinetic analysis with human leucocyte proteinases. Biochem J. 1985 Jan 15;225(2):463–472. doi: 10.1042/bj2250463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Smith C. E., Stack M. S., Johnson D. A. Ozone effects on inhibitors of human neutrophil proteinases. Arch Biochem Biophys. 1987 Feb 15;253(1):146–155. doi: 10.1016/0003-9861(87)90647-3. [DOI] [PubMed] [Google Scholar]
  34. Snider G. L. Chronic obstructive pulmonary disease: risk factors, pathophysiology and pathogenesis. Annu Rev Med. 1989;40:411–429. doi: 10.1146/annurev.me.40.020189.002211. [DOI] [PubMed] [Google Scholar]
  35. Snider G. L., Lucey E. C., Christensen T. G., Stone P. J., Calore J. D., Catanese A., Franzblau C. Emphysema and bronchial secretory cell metaplasia induced in hamsters by human neutrophil products. Am Rev Respir Dis. 1984 Jan;129(1):155–160. doi: 10.1164/arrd.1984.129.1.155. [DOI] [PubMed] [Google Scholar]
  36. Suter S., Schaad U. B., Tegner H., Ohlsson K., Desgrandchamps D., Waldvogel F. A. Levels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: effect of antimicrobial treatment against Pseudomonas aeruginosa. J Infect Dis. 1986 May;153(5):902–909. doi: 10.1093/infdis/153.5.902. [DOI] [PubMed] [Google Scholar]
  37. Thompson R. C., Ohlsson K. Isolation, properties, and complete amino acid sequence of human secretory leukocyte protease inhibitor, a potent inhibitor of leukocyte elastase. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6692–6696. doi: 10.1073/pnas.83.18.6692. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Vogelmeier C., Buhl R., Hoyt R. F., Wilson E., Fells G. A., Hubbard R. C., Schnebli H. P., Thompson R. C., Crystal R. G. Aerosolization of recombinant SLPI to augment antineutrophil elastase protection of pulmonary epithelium. J Appl Physiol (1985) 1990 Nov;69(5):1843–1848. doi: 10.1152/jappl.1990.69.5.1843. [DOI] [PubMed] [Google Scholar]
  39. Warshawski F. J., Sibbald W. J., Driedger A. A., Cheung H. Abnormal neutrophil-pulmonary interaction in the adult respiratory distress syndrome. Qualitative and quantitative assessment of pulmonary neutrophil kinetics in humans with in vivo 111indium neutrophil scintigraphy. Am Rev Respir Dis. 1986 May;133(5):797–804. [PubMed] [Google Scholar]
  40. Weiss S. J., Regiani S. Neutrophils degrade subendothelial matrices in the presence of alpha-1-proteinase inhibitor. Cooperative use of lysosomal proteinases and oxygen metabolites. J Clin Invest. 1984 May;73(5):1297–1303. doi: 10.1172/JCI111332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Weitz J. I., Huang A. J., Landman S. L., Nicholson S. C., Silverstein S. C. Elastase-mediated fibrinogenolysis by chemoattractant-stimulated neutrophils occurs in the presence of physiologic concentrations of antiproteinases. J Exp Med. 1987 Dec 1;166(6):1836–1850. doi: 10.1084/jem.166.6.1836. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES