Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice

• Published in: PloS one Vol. 9; no. 5; p. e96913
• Main Authors: Duarte, Sergio, Kato, Hiroyuki, Kuriyama, Naohisa, Suko, Kathryn, Ishikawa, Tomo-O, Busuttil, Ronald W, Herschman, Harvey R, Coito, Ana J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.05.2014; Public Library of Science (PLoS)
• Subjects: Animals; Biology and Life Sciences; Celecoxib; Cell cycle; Clonal deletion; COX-2 inhibitors; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Gelatinase B; Gene expression; Health aspects; Heart attack; Hepatocytes; Hepatology; Histology; Infiltration; Interleukin 6; Ischemia; Kinases; Laboratory animals; Leukocytes; Lipopolysaccharides; Liver; Liver diseases; Liver Diseases - enzymology; Macrophages; Macrophages - metabolism; Matrix metalloproteinase; Medicine; Medicine and Health Sciences; Metalloproteinase; Mice; Myeloid cells; Myeloid Cells - enzymology; Myocardial infarction; Nitric oxide; Pharmacology; Proteins; Reperfusion; Reperfusion injury; Reperfusion Injury - enzymology; Research and Analysis Methods; Rodents; Stroke; Surgery; Transaminases; Transplants & implants; Los Angeles California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0096913

Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.