Antecedent Hydrogen Sulfide Elicits An Anti-inflammatory Phenotype In Postischemic Murine Small Intestine

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Author: Mozow Yusof

Adviser: Ronald Korthuis

Pharmacology, PhD
FS 2007

 

Public Abstract: Ischemia followed by reperfusion (I/R) is now well-recognized as one form of acute inflammation in whichleukocytes play a key role. Recognition of the importance of the inflammatory process to the pathogenesisof I/R injury has led to an intensive research effort directed at identifying strategies to prevent leukocyteinfiltration into post-ischemic tissues. Preconditioning is a phenomenon through which antecedentexposure to a particular stimulus confers protection against a subsequent prolonged ischemic event. Thedevelopment of a protected phenotype occurs in response to a diverse array of preconditioning stimuli;each of these preconditioning stimuli appears to promote the production of the gaseous monoxide, nitricoxide (NO), as an initial triggering event in the acquisition of tolerance to I/R. Recent work has shown thatNO acts as an endogenous regulator of a second gaseous signaling molecule with vasorelaxant properties,hydrogen sulfide (H2S). While it had been assumed that H2S acts solely as a toxic, environmentalpollutant with minimal physiological and pathophysiological significance, it is now apparent that H2S is alsosynthesized endogenously in mammalian tissue. These observations suggest that, like NO, H2S has theability to fulfill a physiologic role in regulating cardiovascular function, distinct from its toxicologic effect. Inlight of these observations, we postulated that H2S inhibits inflammation after I/R injury, through fourseparate, yet not necessarily distinct, mechanisms. The aims of this dissertation addressed the hypothesisthat H2S elicits a preconditioning stimulus and protects against ischemia/reperfusion (I/R) injury through aneNOS-/p38 MAPK-/K channel-/HO-1 dependent mechanism.