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Published on: August 7, 2012
Effects of selective cyclooxygenase inhibitors on ischemia/reperfusion-induced hepatic microcirculatory dysfunction
1Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan. yoshiya@email.arizona.edu
Abstract:
We examined the effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-alpha also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-alpha. Moreover, the effects of the thromboxane (TX) A(2) (TXA(2)) synthase inhibitor OKY-046 and the TXA(2) receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-alpha production, and that TXs derived from COX are partly responsible for I/R-induced liver injury.
Insights
Selective cyclooxygenase (COX) inhibition protects against liver injury caused by warm ischemia/reperfusion (I/R). COX inhibitors reduced inflammation and liver damage, suggesting a role for thromboxanes in I/R-induced liver injury.
Area of Science:
- Hepatology
- Inflammation Research
- Vascular Biology
Background:
- Hepatic warm ischemia/reperfusion (I/R) injury is a significant clinical challenge.
- Cyclooxygenase (COX) enzymes and their products, like thromboxanes (TXs), are implicated in inflammatory processes.
- The specific roles of COX-1 and COX-2 in I/R-induced liver injury require further elucidation.
Purpose of the Study:
- To investigate the protective effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in a mouse model.
- To determine the contribution of COX-1 and COX-2 pathways to I/R-induced liver damage and inflammation.
- To explore the involvement of thromboxane (TX) pathways in mediating I/R injury.
Main Methods:
- Administration of selective COX-1 (SC-560) and COX-2 (NS-398, celecoxib) inhibitors, indomethacin, a TXA2 synthase inhibitor (OKY-046), and a TXA2 receptor antagonist (S-1452) prior to inducing hepatic I/R in mice.
- In vivo microscopic assessment of hepatic microcirculation, including leukocyte adhesion.
- Measurement of plasma alanine transaminase (ALT) and tumor necrosis factor-alpha (TNF-alpha) levels as markers of liver injury and inflammation.
Main Results:
- Ischemia/reperfusion (I/R) significantly increased leukocyte adhesion in hepatic microvessels and elevated plasma ALT and TNF-alpha levels.
- All tested COX inhibitors (SC-560, NS-398, celecoxib, indomethacin) significantly attenuated I/R-induced microcirculatory dysfunction, liver injury, and TNF-alpha release.
- Inhibition of thromboxane (TX) A2 (TXA2) synthesis or receptor antagonism yielded results comparable to COX inhibition, indicating TXs' role in I/R injury.
Conclusions:
- Both COX-1 and COX-2 pathways contribute to hepatic microvascular and hepatocellular injury during I/R.
- Tumor necrosis factor-alpha (TNF-alpha) production is partially mediated by COX enzymes in I/R injury.
- Thromboxanes (TXs) derived from COX activity play a significant role in the pathogenesis of I/R-induced liver injury, suggesting therapeutic potential for targeting these pathways.
