Carbon monoxide induces cytoprotection in rat orthotopic lung transplantation via anti-inflammatory and anti-apoptotic effects

Ruiping Song, Masatoshi Kubo, Danielle Morse, Zhihong Zhou, Xuchen Zhang, James H. Dauber, James Fabisiak, Sean M. Alber, Simon C. Watkins, Brian S. Zuckerbraun, Leo E. Otterbein, Wen Ning, Tim D. Oury, Patty J. Lee, Kenneth R. McCurry, Augustine M.K. Choi

Research output: Contribution to journalArticle

185 Scopus citations

Abstract

Successful lung transplantation has been limited by the high incidence of acute graft rejection. There is mounting evidence that the stress response gene heme oxygenase-1 (HO-1) and/or its catalytic by-product carbon monoxide (CO) confers cytoprotection against tissue and cellular injury. This led us to hypothesize that CO may protect against lung transplant rejection via its anti-inflammatory and anti-apoptotic effects. Orthotopic left lung transplantation was performed in Lewis rat recipients from Brown-Norway rat donors. HO-1 mRNA and protein expression were markedly induced in transplanted rat lungs compared to sham-operated control lungs. Transplanted lungs developed severe intraalveolar hemorrhage, marked infiltration of inflammatory cells, and intravascular coagulation. However, in the presence of CO exposure (500 ppm), the gross anatomy and histology of transplanted lungs showed marked preservation. Furthermore, transplanted lungs displayed increased apoptotic cell death compared with the transplanted lungs of CO-exposed recipients, as assessed by TUNEL and caspase-3 immunostaining. CO exposure inhibited the induction of IL-6 mRNA and protein expression in lung and serum, respectively. Gene array analysis revealed that CO also down-regulated other proinflammatory genes, including MIP-1α and MIF, and growth factors such as platelet-derived growth factor, which were up-regulated by transplantation. These data suggest that the anti-inflammatory and antiapoptotic properties of CO confer potent cytoprotection in a rat model of lung transplantation.

Original languageEnglish (US)
Pages (from-to)231-242
Number of pages12
JournalAmerican Journal of Pathology
Volume163
Issue number1
DOIs
StatePublished - Jul 1 2003

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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