Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver.

Judit K. Sarady, Brian S. Zuckerbraun, Martin Bilban, Oswald Wagner, Anny Usheva, Fang Liu, Emeka Ifedigbo, Ruben Zamora, Augustine M.K. Choi, Leo E. Otterbein

Research output: Contribution to journalArticle

154 Scopus citations

Abstract

Carbon monoxide (CO) has recently emerged as having potent cytoprotective properties; the mechanisms underlying these effects, however, are just beginning to be elucidated. In a rat model of lipopolysaccharide (LPS)-induced multiorgan failure, we demonstrate that exposure to a low concentration of CO for only 1 h imparts a potent defense against lethal endotoxemia and effectively abrogates the inflammatory response. Exposure to CO leads to long-term survival of >80% of animals vs. 20% in controls. In the lung, CO suppressed LPS-induced lung alveolitis and associated edema formation, while in the liver, it reduced expression of serum alanine aminotransferase, a marker of liver injury. This protection appears to be based in part on different mechanisms in the lung and liver in that CO had reciprocal effects on LPS-induced expression of iNOS and NO production, important mediators in the response to LPS. CO prevented the up-regulation of iNOS and NO in the lung while augmenting expression of iNOS and NO in the liver. Studies of primary lung macrophages and hepatocytes in vitro revealed a similar effect; CO inhibited LPS-induced cytokine production in lung macrophages while reducing LPS-induced iNOS expression and nitrite accumulation and protected hepatocytes from apoptosis while augmenting iNOS expression. Although it is unclear to which extent these changes in iNOS contribute to the cytoprotection conferred by CO, it is fascinating that in each organ CO influences iNOS in a manner known to be protective in that organ: NO is therapeutic in the liver while it is damaging in the lung.

Original languageEnglish (US)
Pages (from-to)854-856
Number of pages3
JournalThe FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume18
Issue number7
DOIs
StatePublished - May 2004

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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