title: Hepatic ischemia and reperfusion injury in the absence of myeloid cell-derived COX-2 in mice.
abstract: 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.
authors.affiliation: Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
authors.forename: Sergio
authors.initials: S
authors.lastname: Duarte
authors.affiliation: Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.affiliation: Present address: Department of Hepatobiliary Pancreatic Surgery, Mie University Graduate School of Medicine, Mie, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Kuriyama
authors.affiliation: Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Suko
authors.affiliation: Present address: Mouse Group, Genomics Business Department, Transgenic Inc., Kobe, Japan.
authors.forename: Tomo-O
authors.initials: TO
authors.lastname: Ishikawa
authors.affiliation: Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.affiliation: Department of Molecular and Medical Pharmacology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Department of Surgery, The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, California, United States.
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D008107:Liver Diseases / Q000201:enzymology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000201:enzymology*; D015427:Reperfusion Injury / Q000201:enzymology*
chemical_list: D051546:Cyclooxygenase 2