Caspase-1 and Inflammasome Activation in Traumahemorrhagic Shock

描述(申请人提供)：控制炎症和细胞损伤是预防和治疗创伤后多器官衰竭(MOF)的关键。然而，许多调节特定器官的炎症和细胞死亡的机制仍不清楚。这意味着，尽管在MOF患者的支持措施方面取得了进展，但在MOF治疗方面，或者在我们充分预防MOF发病的能力方面，进展甚微。我们的首要目标是最终开发基于调控创伤和失血性休克(HS)后的炎症反应及其对细胞死亡和生存途径的影响的创伤患者的新疗法。在这项提案中，我们将继续研究HS后导致终末器官，特别是肝脏中caspase-1激活的分子途径。我们还将确定caspase-1激活如何调节自噬和凋亡，这反过来又决定器官细胞的存活。了解这些细胞信号通路的功能和相互作用有助于我们找到未来预防和治疗创伤后多器官功能衰竭的治疗靶点。我们的初步数据表明，caspase-1在创伤/HS和氧化应激过程中在肝脏中扮演了新的角色。我们发现caspase-1是创伤/HS后肝脏自噬的中心调节因子。重要的是，我们已经证明，caspase-1的激活在创伤/HS后具有肝脏保护作用，这种激活方式独立于caspase-1激活的细胞因子(IL1b/IL18)或主要炎症体成分NLRP3。这些发现挑战了caspase-1通过NLRP3-炎症体被活性氧物种(ROS)等危险信号激活的范式。这些初步的发现使我们得出了主要的假设，即caspase-1的激活是通过细胞类型特定的机制发生的，并且caspase-1的功能在这些细胞类型中也不同。我们已经证明，在HS诱导的氧化应激过程中，caspase-1是调节肝细胞生存途径的中心。如果没有caspase-1，或者caspase-1的激活受到抑制，肝细胞就不能启动自噬等细胞生存策略来应对HS。这会增加细胞的凋亡性或坏死性死亡，增加器官损伤和衰竭的程度。我们希望证明caspase-1的激活途径在HS后不同，并且是细胞类型依赖的。我们还希望证明caspase-1在细胞中具有多种新的功能，在这些细胞中，IL1b/IL18炎性细胞因子的产生不是创伤的主要反应。了解这些在单个细胞类型和器官中的炎症激活和功能的新途径可能有助于我们找到未来治疗和预防创伤患者多器官功能衰竭的新方法。

DESCRIPTION (provided by applicant): 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 (HS). In this proposal we will continue to investigate molecular pathways following HS that lead to activation of caspase-1 in end-organs, particularly liver. We will also determine how caspase-1 activation regulates autophagy and apoptosis, which in turn determines organ cell survival. Knowing how these cell-signaling pathways function and interact may help us to find future therapeutic targets for prevention and treatment of MOF after trauma. Our preliminary data suggest novel roles for caspase-1 in the liver during trauma/HS and during oxidative stresses. We have found that caspase-1 is a central regulator of autophagy in the liver following trauma/HS. Importantly, we have shown that caspase-1 activation is hepatoprotective after trauma/HS, in a manner independent of caspase-1-activated cytokines (IL1b/IL18) or a main inflammasome component, NLRP3. These findings challenge the paradigm that activation of caspase-1 by danger signals such as reactive oxygen species (ROS) occurs via the NLRP3-inflammasome. These preliminary findings lead us to our main hypothesis that caspase-1 activation occurs by cell-type specific mechanisms, and that caspase-1 function also differs in these cell types. We have shown that caspase-1 is central to the regulation of liver cell survival pathways during oxidative stress induced by HS. Without caspase-1, or where caspase-1 activation is inhibited, hepatocytes are less able to initiate cell survival strategies such as autophagy in response to HS. This results in increased apoptotic or necrotic cell death and increased levels of organ damage and failure. We expect to show that caspase-1 activation pathways differ after HS and are cell-type dependent. We also expect to show that caspase-1 has multiple novel functions in cells where production of IL1b/IL18 inflammatory cytokines is not the primary response to trauma. Understanding these novel pathways of inflammatory activation and function in individual cell types and organs may help us find new ways to treat and prevent MOF in trauma patients in the future.