Innate immunity and cardiovascular function in sepsis

描述(由申请人提供)：危重患者经常出现复杂的疾病谱，包括败血症综合征和/或感染性休克。危重病人延迟死亡的一个主要原因是多器官功能障碍综合征(MODS)。目前的研究表明，MODS与先天免疫功能失调有关，先天免疫功能失调可导致弥漫性组织损伤的高炎性休克样状态，以及易发生机会性感染的长时间免疫抑制。败血症/感染性休克/MODS患者存在心肌功能障碍是众所周知的。最近的证据表明，先天免疫反应在脓毒症/感染性休克时心功能不全的病理生理学中起着核心作用。然而，先天免疫调节心脏功能障碍的机制直到现在才被揭示。此外，败血症/感染性休克试图限制炎症反应、促进心肌细胞存活和维持心血管内环境平衡的生理机制仍不清楚。Toll样受体(Toll-like Receptor，TLR)介导的信号转导在先天和炎症反应的诱导中起着关键作用。我们的初步数据表明，TLR2和TLR4在败血症/感染性休克时对心功能的影响是截然不同的，也就是不同的。我们的数据还表明，调节TLR2/TLR4依赖的信号通路可能是预防/管理脓毒症/感染性休克时心功能不全的有效途径。本申请中概述的实验将测试TLR2和TLR4信号通路的差异调制决定败血症/感染性休克损伤时心功能命运的假设。为了验证这一假设，我们将追求三个具体目标。1.我们将阐明TLR4缺乏减轻脓毒症/感染性休克心功能障碍的机制2.我们将明确TLR2调节改善脓毒症/感染性休克心功能的机制。3.我们将研究TLR2/4和PI3K/Akt信号通路的差异调控是否在败血症/感染性休克的心脏保护中起到相加作用。这些研究将提供对脓毒症中对心肌功能和/或功能障碍至关重要的信号通路的机制理解。也有可能以实用的方式应用这一知识，以确定新的治疗方法来预防或管理败血症/感染性休克的心功能障碍。公共卫生相关性：危重患者经常出现复杂的疾病谱，可能包括急性呼吸窘迫综合征(ARDS)、全身炎症反应综合征(SIRS)、脓毒症综合征和/或感染性休克和多器官功能障碍综合征(MODS)。在美国，每年约有75万名患者患上败血症综合征。在这些患者中，总死亡率为28.6%(每年约21.5万人死亡)。那些在最初的事件中幸存下来的患者，可能包括创伤，最终可能会死于广泛的器官功能障碍，这些功能障碍可能是急性的，原因是过度炎症反应，或者是更长时间的免疫功能障碍和感染。事实上，败血症是MODS的常见原因。众所周知，心血管功能障碍也与MODS的发病率和死亡率有关。为败血症/感染性休克和多器官功能障碍综合征开发有效的治疗方法已被证明是极其困难的。这在一定程度上是由于我们对脓毒症中介导心功能不全的细胞和分子机制的不完全了解。因此，很明显，更好地了解脓毒症/感染性休克时导致心功能障碍的分子机制对于开发能够降低发病率和死亡率的辅助治疗是至关重要的。这些研究将提供对脓毒症中对心肌功能和/或功能障碍至关重要的细胞信号通路的机制了解。也有可能以实用的方式应用这一知识，以确定新的治疗方法来预防或管理败血症/感染性休克的心功能障碍。

DESCRIPTION (provided by applicant): The critically ill patient frequently develops a complex disease spectrum that includes sepsis syndrome and/or septic shock. A major cause of delayed deaths in the critically ill patient is multiple organ dysfunction syndrome (MODS). Current knowledge suggests that MODS is related to dysregulation of innate immunity which can involve a hyperinflammatory shock like state resulting in disseminated tissue injury as well as a prolong immune suppression that can predispose to opportunistic infections. The presence of myocardial dysfunction in patients with sepsis/septic shock/MODS is well known. Recent evidence indicates that the innate immune response plays a central role in the pathophysiology of cardiac dysfunction in sepsis/septic shock. However, the mechanisms by which innate immunity mediates cardiac dysfunction are only now coming to the light. Furthermore, the physiologic mechanisms that attempt to limit the inflammatory response, promote survival of cardiac myocytes, and maintain cardiovascular homeostasis in sepsis/septic shock remain unclear. Toll-like receptor (TLR)-mediated signaling plays a critical role in the induction of innate and inflammatory responses. Our preliminary data indicate that TLR2 and TLR4 have strikingly different and opposing, i.e. differential, effects on cardiac function during sepsis/septic shock. Our data also suggest that modulation of TLR2/TLR4-dependent signaling pathways may be an effective approach for preventing/managing cardiac dysfunction in sepsis/septic shock. The experiments outlined in this application will test the hypothesis that differential modulation of TLR2 and TLR4 signaling pathways determine the fate of cardiac function in response to sepsis/septic shock insult. To test this hypothesis, we will pursue three specific aims. 1. We will elucidate the mechanisms by which TLR4 deficiency attenuates cardiac dysfunction in sepsis/septic shock 2. We will define the mechanisms by which modulation of TLR2 improves cardiac function in sepsis/septic shock. 3. We will investigate whether differential regulation of TLR2/4 and PI3K/Akt signaling pathways has an additive effect on cardioprotection during sepsis/septic shock. These studies will provide a mechanistic understanding of the signaling pathways that are critical for myocardial function and/or dysfunction in sepsis. It may also be possible to apply this knowledge in a practical fashion to identify new and novel therapeutic approaches to prevent or manage cardiac dysfunction in sepsis/septic shock. PUBLIC HEALTH RELEVANCE: The critically ill patient frequently develops a complex disease spectrum that may include acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), sepsis syndrome and/or septic shock and multiple organ dysfunction syndrome (MODS). In the United States ~750,000 patients/year develop sepsis syndrome. Of these patients, the overall mortality rate is 28.6% (~215,000 deaths/year). Those patients that survive the initial event, which may include trauma, may ultimately succumb to widespread organ dysfunction that can be either acute, due to hyper-inflammatory responses, or more prolonged due immune dysfunction and infection. Indeed, sepsis is a frequent cause of MODS. It is well known that cardiovascular dysfunction is also associated with MODS morbidity and mortality. Attempts at developing effective therapies for sepsis/septic shock and MODS has proven to be exceedingly difficult. This is due, in part, to our incomplete understanding of the cellular and molecular mechanisms that mediate cardiac dysfunction in sepsis. Thus, it is clear that a better understanding of the molecular mechanisms leading to cardiac dysfunction during sepsis/septic shock is essential in developing adjunctive therapies that could decrease both morbidity and mortality. These studies will provide a mechanistic understanding of the cellular signaling pathways that are critical for myocardial function and/or dysfunction in sepsis. It may also be possible to apply this knowledge in a practical fashion to identify new and novel therapeutic approaches to prevent or manage cardiac dysfunction in sepsis/septic shock.