Molecular cloning and regulation of rat tissue inhibitor of metalloproteinase-2 in acute lung injury in rats

T. S. Gipson*, T. P. Shanley, M. L. Jones, K. J. Johnson, P. A. Ward

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

In inflammatory lung diseases, matrix metalloproteinases (collagenase, gelatinase, stromelysin) play a role in tissue injury. Tissue inhibitor of metalloproteinases (TIMP-2) is an inhibitor of matrix metalloproteinases. The regulatory role of rat tissue inhibitor of metalloproteinase-2 (TIMP-2) in the pathogenesis of acute lung injury in rats after intrapulmonary deposition of IgG immune complexes has been assessed. We cloned the gene for rat TIMP-2 in an effort to gain insight into mechanisms regulating its expression, and ultimately to delineate the role of this proteinase inhibitor during acute lung injury. The rat inhibitor shared 96% and 92% homology with the published murine and human TIMP-2 sequences at the nucleotide level, respectively, and 98% and 97% homology with murine and human TIMP-2 at the amino acid level, respectively. Rat TIMP-2 mRNA and protein expression were determined as a function of time in the IgG immune complex induced lung injury model. A time-dependent increase in TIMP-2 mRNA in lung extracts was observed. TIMP-2 protein could also be detected in bronchoalveolar lavage (BAL) fluids by western blot analysis in IgG-immune complex lung injury model. Anti-TIMP-2 administered at commencement of IgG immune complex induced injury resulted in significant increase in BAL neutrophils as well as in injury as measured by pulmonary vascular permeability. Under these conditions, in the IgG immune complex induced injury model TNF-alpha content in BAL fluids was unaltered. These findings suggest that rat TIMP-2 plays an important role inflammatory disease states. The instillation of anti-TIMP-2 intratracheally causes increased lung injury in rats.

Original languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number6
StatePublished - Dec 1 1996

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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