Lung transplant ischemia reperfusion injury: Metalloprotease inhibition down-regulates exposure of type V collagen, growth-related oncogene-induced neutrophil chemotaxis, and tumor necrosis factor-α expression

Takekazu Iwata, Masako Chiyo, Shigetoshi Yoshida, Gerald N. Smith, Elizabeth A. Mickler, Robert Presson, Amanda J. Fisher, David D. Brand, Oscar W. Cummings, David S. Wilkes

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Background. Immunity to type V collagen [col(V)] contributes to lung transplant rejection. Matrix metalloproteases (MMPs), which are induced by transplant-related ischemia-reperfusion injury (IRI), could expose col(V) and regulate local IRI-induced inflammation. Methods. To test the hypothesis that MMPs induce col(V) exposure and inflammation, Wistar-Kyoto rats were treated with the MMP inhibitor, COL-3, before inducing lung IRI without transplantation, and in parallel studies, Wistar-Kyoto lung donor and recipients were treated with COL-3 pre- and postisograft lung transplantation. Results. Ischemia-reperfusion injury induced growth-related oncogene/CINC-1-dependent neutrophil influx, and upregulated tumor necrosis factor-α. MMP2 and MMP9, induced at 4 and 24 hr after IRI, respectively, were associated with detection of antigenic col(V) in bronchoalveolar lavage and lung interstitium because of MMP-mediated matrix degradation. MMP-inhibitor treatment significantly reduced polymorphonuclear leukocytes, growth-related oncogene/CINC-1, and tumor necrosis factor-α; abrogated MMP-9 expression; and resulted in lower levels of antigenic col(V) in bronchoalveolar lavage. In the lung transplant model, inhibiting MMPs in the donor before lung harvest and in the recipient after lung transplantation resulted in improved oxygenation and diminished polymorphonuclear leukocyte influx into the isograft. Conclusion.MMP inhibition may be a potential therapy to prevent release of antigenic col(V) and ameliorate IRI in the transplant recipient.

Original languageEnglish (US)
Pages (from-to)417-426
Number of pages10
JournalTransplantation
Volume85
Issue number3
DOIs
StatePublished - Feb 1 2008

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Keywords

  • Chemokines
  • Cytokines
  • Graft rejection
  • Lung transplantation
  • MMPs
  • Type V collagen

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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