Calcium: a regulator of the inflammatory response in endotoxemia and sepsis.
Calcium functions as a critical intracellular second messenger and regulates many cellular processes such as muscle contractility, glycogen and protein turnover, hormone secretion, and vascular smooth muscle tone which are markedly abnormal during sepsis/endotoxemia. There also is increasing recognition of the role of calcium in the production of a variety of cytokines such as tumor necrosis factor alpha and interleukin-1 beta, which are important mediators of sepsis. Our hypothesis is that disturbances in cellular calcium regulation are responsible for or contribute to many of the metabolic manifestations of sepsis/endotoxemia and may be the driving force behind the development of multiorgan failure. In this article, we focus on a) new insights into calcium's regulation of the inflammatory cascade, b) the controversy concerning whether free cytosolic calcium concentration ([Ca2+]i) is increased in the disorder, and c) the potential therapeutic uses of calcium antagonists. An important message is that there are fundamental differences in the pathophysiology of the endotoxin model versus the cecal ligation and perforation (CLP) model of sepsis. Although calcium antagonists improve survival in the endotoxin model, they increase mortality in the CLP model of sepsis. Possible reasons for the differences in the effect of the drugs in the two different models and insight into the mechanisms of cell injury in endotoxin versus sepsis are presented.
Hotchkiss
R S
RS
Department of Anesthesiology, Washington University, St. Louis, MO, USA.
Karl
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IE
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D016207:Cytokines / Q000502:physiology; D004731:Endotoxins / Q000097:blood*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*; D012772:Shock, Septic / Q000188:drug therapy / Q000503:physiopathology*
D002121:Calcium Channel Blockers; D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D002118:Calcium