Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury

Teletha S. Gipson, Nicolas M. Bless, Thomas P. Shanley, Larry D. Crouch, Michael R. Bleavins, Ellen M. Younkin, Vidya Sarma, Douglas F. Gibbs, Wongelawit Tefera, Patrick C. McConnell, William T. Mueller, Kent J. Johnson, Peter A. Ward

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

Inflammatory lung injury is probably regulated by the balance between proteases and protease inhibitors together with oxidants and antioxidants, and proinflammatory and anti-inflammatory cytokines. Rat tissue inhibitor of metalloprotease-2 (TIMP-2) and secreted leukoprotease inhibitor (SLPI) were cloned, expressed, and shown to be up-regulated at the levels of mRNA and protein during lung inflammation in rats induced by deposition of IgG immune complexes. Using immunoaffinity techniques, endogenous TIMP-2 in the inflamed lung was shown to exist as a complex with 72- and 92-kDa metalloproteinases (MMP-2 and MMP-9). In inflamed lung both TIMP-2 and SLPI appeared to exist as enzyme inhibitor complexes. Lung expression of both TIMP-2 and SLPI appeared to involve endothelial and epithelial cells as well as macrophages. To assess how these endogenous inhibitors might affect the lung inflammatory response, animals were treated with polyclonal rabbit Abs to rat TIMP-2 or SLPI. This intervention resulted in significant intensification of lung injury (as revealed by extravascular leak of albumin) and substantially increased neutrophil accumulation, as determined by cell content in bronchoalveolar lavage (BAL) fluids. These events were correlated with increased levels of C5a-related chemotactic activity in BAL fluids, while BAL levels of TNF-α and chemokines were not affected by treatment with anti-TIMP-2 or anti-SLPI. The data suggest that endogenous TIMP-2 and SLPI dynamically regulate the intensity of lung inflammatory injury, doing so at least in part by affecting the generation of the inflammatory mediator, C5a.

Original languageEnglish (US)
Pages (from-to)3653-3662
Number of pages10
JournalJournal of Immunology
Volume162
Issue number6
StatePublished - Mar 15 1999

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Acute Lung Injury
Metalloproteases
Protease Inhibitors
Lung Injury
Lung
Bronchoalveolar Lavage Fluid
Matrix Metalloproteinase 2
Bronchoalveolar Lavage
Enzyme Inhibitors
Antigen-Antibody Complex
Matrix Metalloproteinases
Chemokines
Oxidants
Albumins
Pneumonia
Neutrophils
Peptide Hydrolases
Anti-Inflammatory Agents
Endothelial Cells
Antioxidants

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Gipson, T. S., Bless, N. M., Shanley, T. P., Crouch, L. D., Bleavins, M. R., Younkin, E. M., ... Ward, P. A. (1999). Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury. Journal of Immunology, 162(6), 3653-3662.

Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury. / Gipson, Teletha S.; Bless, Nicolas M.; Shanley, Thomas P.; Crouch, Larry D.; Bleavins, Michael R.; Younkin, Ellen M.; Sarma, Vidya; Gibbs, Douglas F.; Tefera, Wongelawit; McConnell, Patrick C.; Mueller, William T.; Johnson, Kent J.; Ward, Peter A.

In: Journal of Immunology, Vol. 162, No. 6, 15.03.1999, p. 3653-3662.

Research output: Contribution to journalArticle

Gipson, TS, Bless, NM, Shanley, TP, Crouch, LD, Bleavins, MR, Younkin, EM, Sarma, V, Gibbs, DF, Tefera, W, McConnell, PC, Mueller, WT, Johnson, KJ & Ward, PA 1999, 'Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury', Journal of Immunology, vol. 162, no. 6, pp. 3653-3662.
Gipson TS, Bless NM, Shanley TP, Crouch LD, Bleavins MR, Younkin EM et al. Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury. Journal of Immunology. 1999 Mar 15;162(6):3653-3662.
Gipson, Teletha S. ; Bless, Nicolas M. ; Shanley, Thomas P. ; Crouch, Larry D. ; Bleavins, Michael R. ; Younkin, Ellen M. ; Sarma, Vidya ; Gibbs, Douglas F. ; Tefera, Wongelawit ; McConnell, Patrick C. ; Mueller, William T. ; Johnson, Kent J. ; Ward, Peter A. / Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury. In: Journal of Immunology. 1999 ; Vol. 162, No. 6. pp. 3653-3662.
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