| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
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
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-xL 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by the National Institutes of Health Grant R01 AIO57832 (to A.J.C.).
2 Current address: Kitasato University School of Medicine, Kanagawa, Japan.
3 Address correspondence and reprint requests to Dr. Ana J. Coito, The Dumont–University of California Los Angeles Transplant Center, 77-120 CHS, Box 957054, Los Angeles, CA 90095. E-mail address: acoito{at}mednet.ucla.edu
4 Abbreviations used in this paper: I/R, ischemia/reperfusion; COX, cyclooxygenase; ECM, extracellular matrix; iNOS, inducible NO synthase; KO, knockout; MPO, myeloperoxidase; ND, nondetectable; PGI2, prostacyclin; sGOT, serum glutamic-oxaloacetic transaminase; sGPT, serum glutamic-pyruvic transaminase; TXA2, thromboxane A2; WT, wild type; gr, group.
This article has been cited by other articles:
|
|
 |
|
  T. Hamada, S. Duarte, S. Tsuchihashi, R. W. Busuttil, and A. J. Coito Inducible Nitric Oxide Synthase Deficiency Impairs Matrix Metalloproteinase-9 Activity and Disrupts Leukocyte Migration in Hepatic Ischemia/Reperfusion Injury Am. J. Pathol., June 1, 2009; 174(6): 2265 - 2277. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
