Background: Neutrophil adhesion and migration are critical in hepatic ischemia and reperfusion injury (I/R). P-selectin and the intercellular adhesion molecule (ICAM)-1 can mediate neutrophilendothelial cell interactions, neutrophil migration, and the interactions of neutrophils with hepatocytes in the liver. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy in reperfusion injury, indicating that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the aim of this study was to assess the role of P-selectin and ICAM-1 in neutrophil infiltration and liver injury during early and late phases of liver I/R.
BACKGROUND AND PURPOSERecent studies have suggested an essential role for aldehyde dehydrogenase 2 (ALDH2) in the bioactivation of organic nitrates such as glyceryl trinitrate (GTN). In the present study, we utilized an in vivo GTN tolerance model to further investigate the role of ALDH2 in GTN bioactivation and tolerance.
EXPERIMENTAL APPROACHWe assessed changes in aortic ALDH activity, and in ALDH2 protein expression in various rat blood vessels (aorta, vena cava, femoral artery and femoral vein) during continuous GTN exposure (0.4 mg·h -1 for 6, 12, 24 or 48 h) or after a 1-, 3-or 5-day drug-free period following a 48 h exposure to GTN, in relation to changes in vasodilator responses to GTN and in vascular GTN biotransformation.
KEY RESULTSA decrease was observed in both ALDH2 protein expression (80% in tolerant veins and 30% in tolerant arteries after 48 h exposure to GTN) and aortic ALDH activity, concomitant with decreased vasodilator responses to GTN and decreased aortic GTN biotransformation. However, after a 24 h drug-free period following 48 h of GTN exposure, vasodilator responses to GTN and aortic GTN biotransformation activity had returned to control values, whereas vascular ALDH2 expression and aortic ALDH activity were still significantly depressed, and remained so for 3-5 days following cessation of GTN exposure.
CONCLUSIONS AND IMPLICATIONSThe dissociation of reduced ALDH activity and ALDH2 expression from the duration of the impaired vasodilator and biotransformation responses to GTN in nitrate-tolerant blood vessels, suggests that factors other than changes in ALDH2-mediated GTN bioactivation contribute to nitrate tolerance.
AbbreviationsALDH, aldehyde dehydrogenase; DEA/NO, 1,1-diethyl-2-hydroxy-2-nitrosohydrazine; GTN, glyceryl trinitrate; GDN, glyceryl dinitrate; sGC, soluble GC; PETN, pentaerythrityl tetranitrate
Background: The inflammatory response to hepatic ischemia-reperfusion (I/R) is associated with an increase in cytokine production. Studies have documented that sex hormones modulate both the innate and adaptive immune responses, and that females are more robust than males. The aim of this study was to determine whether a sex difference in cytokine response to hepatic I/R exists under normal pathophysiologic condition without hormone intervention.
We recently showed anti‐inflammatory role of cholinergic pathway (Ch.Path) in liver IR by pharmacological stimulation of acetylcholine receptor. Here we tested whether endogenous Ch.Path (e.Ch.Path) activation would exert a similar protective effect, and studied liver gene expression modulation by Ch.Path activation.MethodsMice treated with CCK‐8 or nicotine, i.p. prior to ischemia (CCK‐8 stimulates acetylcholine release via Ch.Path). A 2nd group was subjected to bilateral vagotomy prior to CCK‐8, while a 3rd group subjected to electrical vagal stimulation for 20min, followed by liver IR (90min I : 3h R). Plasma ALT and cytokines levels and liver histopathology were assessed.ResultsCCK‐8‐ or nicotine treatment significantly reduced liver injury (87%, and %69 respectively) and cytokine production, as compared to saline‐treated mice. CCK‐8 protective effect was absent in vagotomized mice, indicating e.Ch.Path role. Electrical vagal nerve stimulation confirmed the observation as ALT levels and liver injury were significantly decreased in this group. Gene array data showed significant modulation of several pathways and associated genes.Conclusionse.Ch.Path activation via humoral or electrical stimuli provides a protective effect on liver IR injury, which could offer therapeutic means to selectively act on targeted genes for treatment of IR inflammatory diseases. Support: NIH HL075475.
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