Ischemia/reperfusion, inflammatory signal transduction and apoptosis: the physiologic signalling role of reactive oxygen metabolites
Year: 1994
Type: article
Abstract: Reactive oxygen metabolites generated initially from xanthine oxidase activated from constituitively-expressed xanthine dehydrogenese by ischemia, generate a substantial component of post-ischemic injury at reperfusion in many organs. The key to these events is the activation of endothelial cell xanthine oxidase by ischemia, causing the oxidantmediated upregulation of endothelial integrins, with the consequent arrest and activation of circulating neutrophils in the venular microvasculature, resulting ultimately in parenchymal organ dysfunction. Because there is no evident natural selective advantage to reperfusion injury (and, indeed, no reperfusion in a natural environment), an obvious question is: What survival advantage provided the natural selective pressure for the evolution of this intricate biochemical process? Evidence from a number of laboratories indicates that endothelial xanthine oxidase can be activated by specific proinflammatory cytokines (TNF, IL-3, C'SA, etc.) and other mediators (endotexin, phorbol esters, oxidants, etc.). These and other data from our laboratory suggest that endothelial dehydrogensse to oxidese activation may well represent the central molecular trigger of reticuloendothelial function, transducing circulating inflammatory signals (cytokines) by means of the generation of reactive oxidants as second messengers to effect the trapping, phagocytosis and killing of circulating microorganisms. The marked induction of xanthine dehydrogenase expression in endothelial cells by yinterferon may represent the priming of this trigger mechanism. Recent evidence suggests that one consequence of this aberrant signal transduction is the activation of specific programs for heat shock gene expression in endothelial cells. This activation preempts constituitive programs of gene expression, resulting in cell death, not by necrosis, but by apoptosis, perhaps due to the preemption of the expression of a constituitive antioxidant like bcl-2, with resultant nucleolysis by ambient endogenous, or exogenous oxidant generation. Reperfusion injury may well represent the aberrant triggering of this antibacterial defense mechanism by ischemia, and apoptosis its pathophysiologic extreme. If this hypothesis proves correct, it provides another of the accumulating examples (eg:NO,C0) by which reactive oxidants function as second messengers to effect physiological signal transduction.
Source: Pathophysiology
Author: Gregory B. Bulkley
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,689
OpenAlex ID: W2011324202