Inflammasome activation in trauma-hemorrhagic shock

项目总结/摘要 控制炎症和细胞损伤是防治多器官功能衰竭的关键 (MOF)创伤后。然而，许多调节炎症和细胞死亡的机制， 具体器官仍不清楚。这意味着，尽管在支持性措施方面取得了进展， 尽管如此，在MOF的治疗方面，或者在我们充分预防MOF发作的能力方面，几乎没有进展。 财政部我们的总体目标是最终为创伤患者开发新的治疗方法， 创伤后炎症反应及其对细胞死亡和存活途径的影响， 失血性休克复苏（HS/R）。在本提案中，我们将继续研究新的分子 HS/R后的途径，导致终末器官，特别是肝脏中caspase-11的激活。我们还将 确定炎症性半胱天冬酶的激活如何调节细胞死亡和炎症， 决定了HS/R后器官细胞的存活。了解这些细胞信号通路的功能和相互作用 可能为我们未来预防和治疗创伤后MOF的治疗目标提供指导。 炎性半胱天冬酶包括半胱天冬酶-1，11（小鼠），4/5（人），并且与 炎性细胞死亡（焦亡）和炎性细胞因子（IL-1β、IL-18）的释放。Caspase-11是 最近被鉴定为脂多糖（LPS）的细胞内受体，并形成所谓的 非典型炎性小体LPS介导的巨噬细胞caspase-11激活导致 gasdermin D（GsdmD）和随后的IL-1β释放，诱导焦亡和启动NLRP 3 炎性小体和caspase-1激活。Caspase-11也可被内源性氧化应激激活。 在LPS引发的树突状细胞中，氧化磷脂（oxPAPC）的相互作用，尽管这种相互作用不会导致细胞凋亡。 我们令人兴奋的新数据表明，caspase-11在HS/R（一种非感染性/无菌损伤模型）期间被激活， 提示内源性损伤相关的caspase-11激活的新机制 分子模式（DAMP），而不需要LPS。我们再一次证明线粒体 在HS/R后炎症反应的激活中不可或缺， 应激线粒体可激活caspase-11。令人惊讶的是，HS/R后HC中caspase-11的活化 不会导致细胞凋亡，但对于外泌体中HC HMGB 1的主动释放和caspase-11的激活至关重要 在HS/R中是有害的。我们的初步发现使我们得出了我们的主要假设，即DAMP诱导的 caspase-11的激活在HS/R过程中具有细胞特异性功能，是细胞凋亡的重要调节因子， 死亡和器官损伤 我们希望证实新的，线粒体DAMP介导的caspase-11激活途径， caspase-11在肝脏中的功能可能使其成为创伤/HS期间有吸引力的治疗靶点。

PROJECT SUMMARY/ABSTRACT Controlling inflammation and cellular damage is the key to preventing and treating multiple organ failure (MOF) following trauma. However, many of the mechanisms that regulate inflammation and cell death in specific organs remain unknown. This means that despite advances in supportive measures for patients with MOF, there have been few advances in MOF treatments, or in our ability to adequately prevent the onset of MOF. Our overarching goal is to ultimately develop new therapeutics for trauma patients based on regulating the inflammatory response and its effects on cellular death and survival pathways following trauma and hemorrhagic shock with resuscitation (HS/R). In this proposal we will continue to investigate novel molecular pathways following HS/R that lead to activation of caspase-11 in end-organs, particularly liver. We will also determine how activation of inflammatory caspases regulates cell death and inflammation, which in turn determines organ cell survival after HS/R. Knowing how these cell-signaling pathways function and interact may guide us toward future therapeutic targets for prevention and treatment of MOF after trauma. Inflammatory caspases include caspases-1, 11 (mice), 4/5 (human), and are associated with inflammatory cell death (pyroptosis) and release of inflammatory cytokines (IL-1β, IL-18). Caspase-11 was recently identified as the intracellular receptor for lipopolysaccharide (LPS) and forms what has been termed the non-canonical inflammasome. LPS-mediated caspase-11 activation in macrophages results in cleavage of gasdermin D (GsdmD) and subsequent release of IL-1β, induction of pyroptosis, and initiation of NLRP3 inflammasome and caspase-1 activation. Caspase-11 can also be activated by endogenous oxidized phospholipid (oxPAPC) in LPS-primed dendritic cells, although this interaction does not result in pyroptosis. Our exciting new data show that caspase-11 is activated during HS/R, a non-infectious/sterile injury model, suggesting a novel mechanism of activation of caspase-11 by endogenous damage associated molecular patterns (DAMPs) without a requirement for LPS. We show that once again mitochondria are integral in activation of inflammatory responses after HS/R, and cardiolipin externalization on damaged and stressed mitochondria can activate caspase-11. Surprisingly activation of caspase-11 in HC after HS/R does not lead to pyroptosis, but is vital for active release of HC HMGB1 in exosomes, and caspase-11 activation is detrimental in HS/R. Our preliminary findings lead us to our main hypothesis that DAMP-induced caspase-11 activation has cell specific functions during HS/R, and is an important regulator of cell death and organ damage. We expect to confirm novel, mitochondrial DAMP-mediated pathways of activation of caspase-11, and novel functions of caspase-11 in liver that may make it an attractive therapeutic target during trauma/HS.