title: Cyclooxygenase-2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury.
abstract: Cyclooxygenase-2 (COX-2) is a prostanoid-synthesizing enzyme that is critically implicated in a variety of pathophysiological processes. Using a COX-2-deficient mouse model, we present data that suggest that COX-2 has an active role in liver ischemia/reperfusion (I/R) injury. We demonstrate that COX-2-deficient mice had a significant reduction in liver damage after I/R insult. The inability of COX-2(-/-) to elaborate COX-2 products favored a Th2-type response in these mice. COX-2(-/-) livers after I/R injury showed significantly decreased levels of IL-2, as well as IL-12, a cytokine known to have a central role in Th1 effector cell differentiation. Moreover, such livers expressed enhanced levels of the anti-inflammatory cytokine IL-10, shifting the balance in favor of a Th2 response in COX-2-deficient mice. The lack of COX-2 expression resulted in decreased levels of CXCL2, a neutrophil-activating chemokine, reduced infiltration of MMP-9-positive neutrophils, and impaired late macrophage activation in livers after I/R injury. Additionally, Bcl-2 and Bcl-x(L) were normally expressed in COX-2(-/-) livers after injury, whereas respective wild-type controls were almost depleted of these two inhibitors of cell death. In contrast, caspase-3 activation and TUNEL-positive cells were depressed in COX-2(-/-) livers. Therefore, our data support the concept that COX-2 is involved in the pathogenic events occurring in liver I/R injury. The data also suggest that potential valuable therapeutic approaches in liver I/R injury may result from further studies aimed at identifying specific COX-2-derived prostanoid pathways.
authors.affiliation: The Dumont-University of California Los Angeles Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamada
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Tsuchihashi
authors.forename: Armine
authors.initials: A
authors.lastname: Avanesyan
authors.forename: Sergio
authors.initials: S
authors.lastname: Duarte
authors.forename: Carolina
authors.initials: C
authors.lastname: Moore
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: Ana J
authors.initials: AJ
authors.lastname: Coito
mesh_terms: D000818:Animals; D000068579:Celecoxib; D054426:Chemokine CXCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D008099:Liver / Q000098:blood supply* / Q000201:enzymology / Q000276:immunology*; D008262:Macrophage Activation; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage; D015427:Reperfusion Injury / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D013449:Sulfonamides / Q000008:administration & dosage; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D061965:Matrix Metalloproteinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D051020:bcl-X Protein; D051546:Cyclooxygenase 2; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib