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. 1994 Jun;49(6):567–572. doi: 10.1136/thx.49.6.567

Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation.

C G Llewellyn-Jones 1, D A Lomas 1, R A Stockley 1
PMCID: PMC474946  PMID: 7912452

Abstract

BACKGROUND--Neutrophil elastase is able to degrade connective tissue matrices and is thought to be involved in the pathogenesis of destructive lung diseases. METHODS--The ability of recombinant secretory leucoprotease inhibitor (rSLPI) to inhibit neutrophil mediated degradation of fibronectin in vitro is demonstrated and its efficacy compared with native alpha-1-proteinase inhibitor (n alpha 1-PI), recombinant alpha-1-proteinase inhibitor (r alpha 1-PI), and the chemical elastase inhibitor ICI 200,355. RESULTS--When preincubated with neutrophils both rSLPI and r alpha 1-PI were effective inhibitors of fibronectin degradation although n alpha 1-PI and ICI 200,355 were less effective. Recombinant SLPI was the most effective inhibitor when the cells were allowed to adhere to fibronectin before the addition of the inhibitors. Preincubation of rSLPI (0.1 mumol/l) with the fibronectin plate resulted in almost total inhibition of fibronectin degradation (reduced to 3.3 (SE 0.9)% of control). Pretreating the fibronectin plate with 1 mumol/l rSLPI, r alpha 1-PI and ICI 200,355 followed by thorough washing before the addition of cells resulted in no inhibition of fibronectin degradation with r alpha 1-PI and the ICI inhibitor, but rSLPI retained its inhibitory effect. This effect could be reduced by adding rSLPI in high pH buffer or 2 mol/1 NaCl. CONCLUSIONS--It is postulated that rSLPI binds to fibronectin to form a protective layer which prevents its degradation by neutrophil elastase. It may prove to be the most useful therapeutic agent in the prevention of neutrophil mediated lung damage.

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Selected References

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  1. Birrer P., McElvaney N. G., Gillissen A., Hoyt R. F., Bloedow D. C., Hubbard R. C., Crystal R. G. Intravenous recombinant secretory leukoprotease inhibitor augments antineutrophil elastase defense. J Appl Physiol (1985) 1992 Jul;73(1):317–323. doi: 10.1152/jappl.1992.73.1.317. [DOI] [PubMed] [Google Scholar]
  2. Breuer R., Christensen T. G., Niles R. M., Stone P. J., Snider G. L. Human neutrophil elastase causes glycoconjugate release from the epithelial cell surface of hamster trachea in organ culture. Am Rev Respir Dis. 1989 Mar;139(3):779–782. doi: 10.1164/ajrccm/139.3.779. [DOI] [PubMed] [Google Scholar]
  3. Burnett D., Chamba A., Hill S. L., Stockley R. A. Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis. Lancet. 1987 Nov 7;2(8567):1043–1046. doi: 10.1016/s0140-6736(87)91476-0. [DOI] [PubMed] [Google Scholar]
  4. Campbell E. J., Senior R. M., McDonald J. A., Cox D. L. Proteolysis by neutrophils. Relative importance of cell-substrate contact and oxidative inactivation of proteinase inhibitors in vitro. J Clin Invest. 1982 Oct;70(4):845–852. doi: 10.1172/JCI110681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chamba A., Afford S. C., Stockley R. A., Burnett D. Extracellular proteolysis of fibronectin by neutrophils: characterization and the effects of recombinant cytokines. Am J Respir Cell Mol Biol. 1991 Apr;4(4):330–337. doi: 10.1165/ajrcmb/4.4.330. [DOI] [PubMed] [Google Scholar]
  6. Davies P., Ashe B. M., Bonney R. J., Dorn C., Finke P., Fletcher D., Hanlon W. A., Humes J. L., Maycock A., Mumford R. A. The discovery and biologic properties of cephalosporin-based inhibitors of PMN elastase. Ann N Y Acad Sci. 1991;624:219–229. doi: 10.1111/j.1749-6632.1991.tb17021.x. [DOI] [PubMed] [Google Scholar]
  7. Hubbard R. C., Sellers S., Czerski D., Stephens L., Crystal R. G. Biochemical efficacy and safety of monthly augmentation therapy for alpha 1-antitrypsin deficiency. JAMA. 1988 Sep 2;260(9):1259–1264. [PubMed] [Google Scholar]
  8. Jepsen L. V., Skottun T. A rapid one-step method for the isolation of human granulocytes from whole blood. Scand J Clin Lab Invest. 1982 May;42(3):235–238. [PubMed] [Google Scholar]
  9. Kramps J. A., Te Boekhorst A. H., Fransen J. A., Ginsel L. A., Dijkman J. H. Antileukoprotease is associated with elastin fibers in the extracellular matrix of the human lung. An immunoelectron microscopic study. Am Rev Respir Dis. 1989 Aug;140(2):471–476. doi: 10.1164/ajrccm/140.2.471. [DOI] [PubMed] [Google Scholar]
  10. Lomas D. A., Evans D. L., Stone S. R., Chang W. S., Carrell R. W. Effect of the Z mutation on the physical and inhibitory properties of alpha 1-antitrypsin. Biochemistry. 1993 Jan 19;32(2):500–508. doi: 10.1021/bi00053a014. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. McElvaney N. G., Hubbard R. C., Birrer P., Chernick M. S., Caplan D. B., Frank M. M., Crystal R. G. Aerosol alpha 1-antitrypsin treatment for cystic fibrosis. Lancet. 1991 Feb 16;337(8738):392–394. doi: 10.1016/0140-6736(91)91167-s. [DOI] [PubMed] [Google Scholar]
  13. Morrison H. M., Welgus H. G., Stockley R. A., Burnett D., Campbell E. J. Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity. Am J Respir Cell Mol Biol. 1990 Mar;2(3):263–269. doi: 10.1165/ajrcmb/2.3.263. [DOI] [PubMed] [Google Scholar]
  14. Padrines M., Bieth J. G. Elastin decreases the efficiency of neutrophil elastase inhibitors. Am J Respir Cell Mol Biol. 1991 Feb;4(2):187–193. doi: 10.1165/ajrcmb/4.2.187. [DOI] [PubMed] [Google Scholar]
  15. Rao N. V., Marshall B. C., Gray B. H., Hoidal J. R. Interaction of secretory leukocyte protease inhibitor with proteinase-3. Am J Respir Cell Mol Biol. 1993 Jun;8(6):612–616. doi: 10.1165/ajrcmb/8.6.612. [DOI] [PubMed] [Google Scholar]
  16. Reilly C. F., Travis J. The degradation of human lung elastin by neutrophil proteinases. Biochim Biophys Acta. 1980 Jan 24;621(1):147–157. doi: 10.1016/0005-2795(80)90070-7. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Rinehart A. R., Mallya S., Simon S. R. Human alpha 1-proteinase inhibitor binds to extracellular matrix in vitro. Am J Respir Cell Mol Biol. 1993 Dec;9(6):666–679. doi: 10.1165/ajrcmb/9.6.666. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Smallman L. A., Hill S. L., Stockley R. A. Reduction of ciliary beat frequency in vitro by sputum from patients with bronchiectasis: a serine proteinase effect. Thorax. 1984 Sep;39(9):663–667. doi: 10.1136/thx.39.9.663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Snider G. L., Stone P. J., Lucey E. C., Breuer R., Calore J. D., Seshadri T., Catanese A., Maschler R., Schnebli H. P. Eglin-c, a polypeptide derived from the medicinal leech, prevents human neutrophil elastase-induced emphysema and bronchial secretory cell metaplasia in the hamster. Am Rev Respir Dis. 1985 Dec;132(6):1155–1161. doi: 10.1164/arrd.1985.132.6.1155. [DOI] [PubMed] [Google Scholar]
  22. Stolk J., Davies P., Kramps J. A., Dijkman J. H., Humes J. J., Knight W. B., Green B. G., Mumford R., Bonney R. J., Hanlon W. A. Potency of antileukoprotease and alpha 1-antitrypsin to inhibit degradation of fibrinogen by adherent polymorphonuclear leukocytes from normal subjects and patients with chronic granulomatous disease. Am J Respir Cell Mol Biol. 1992 May;6(5):521–526. doi: 10.1165/ajrcmb/6.5.521. [DOI] [PubMed] [Google Scholar]
  23. Stone P. J., Lucey E. C., Snider G. L. Induction and exacerbation of emphysema in hamsters with human neutrophil elastase inactivated reversibly by a peptide boronic acid. Am Rev Respir Dis. 1990 Jan;141(1):47–52. doi: 10.1164/ajrccm/141.1.47. [DOI] [PubMed] [Google Scholar]
  24. Tegner H., Ohlsson K., Toremalm N. G., von Mecklenburg C. Effect of human leukocyte enzymes on tracheal mucosa and its mucociliary activity. Rhinology. 1979 Sep;17(3):199–206. [PubMed] [Google Scholar]

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