orai1cracm1在内毒素引起钙超载中的机制研究-study on the mechanism of orai 1 cracm 1 in calcium overload caused by endotoxin.docx

AbstractEffect of Orai1 on lipopolysaccharide-related calcium overloadBackgroundOne core event to all of the gram-negative bacterial sepsis complications including disseminated intravascular coagulation (DIC), vascular scleratheroma, systemic vascular collapse, multiorgan dysfunctional syndrome (MODS), acute respiratory disgtress syndrome (ARDS) is endothelial cell (EC) injury and dysfunction. The vascular endothelium serves as the key barrier between the intravascular compartment and extravascular tissues and plays a critical role in a large number of physiological and pahtological processes. ECs, integrally involved in regulating blood flow, coagulation, leukocyte trafficking, edema formation, wound healing, and angiogenesis, are constantly exposed to circulating mediators such as bacterial lipopolysaccharide (LPS) or endotoxin, a highly proinflammatory molecule that is a component of the outer envelope of all gram-negative bacteria. Evidence exists that LPS alone or in concert with other endogenous factors, is responsible for much of the EC injury and dysfunction associated with gram-negative sepsis. LPS-induced EC programmed cell death or apoptosis is an event that is believed to contribute to the pathogenesis of sepsis and its complications.More recent studies have shown that alterations in the intracellular Ca2+ homeostasis iscommonly involved in the initiation of apoptosis. Oscillation of intracellular Ca2+, intracellular Ca2+ linking stores such as the endoplasmic reticulum (ER) and/or mitochondria linked to the cytoplasmic membrane or intracellular Ca2+ overload, can cause cytotoxicity and trigger apoptotic cell death, but the mechanism is unclear.Several studies have also revealed that store-operated Ca2+(SOC) influx is the major mechanism for Ca2+ entry in many non-excitable cell types. SOC entry is the process whereby modest ER Ca2+ store depletion leads to activation of the plasma membrane (PM) Ca2+ release-activated channel (CRAC) activation provid