Innate immunity and cardiovascular function in sepsis

脓毒症的先天免疫和心血管功能

• 批准号: 7901577
• 负责人: Chuanfu Li
• 金额: $ 29.73万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901577
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Acute; Adult Respiratory Distress Syndrome; Attenuated; Basic Science; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Clinical; Complex; Critical Illness; Data; Development; Disease; EFRAC; Employee Strikes; Etiology; Event; Figs - dietary; Functional disorder; Goals; Homeostasis; Immune System Diseases; Immune response; Immunosuppression; Infection; Inflammatory; Inflammatory Response; Injury; Investigation; Knowledge; Left; Ligation; Light; Lipopolysaccharides; Maintenance; Mediating; Molecular; Morbidity - disease rate; Multiple Organ Failure; Mus; Myocardial; Myocardial dysfunction; Natural Immunity; Opportunistic Infections; Organ; Patients; Peptidoglycan; Physiological; Play; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Puncture procedure; Regulation; Research; Role; Sepsis; Sepsis Syndrome; Septic Shock; Shock; Signal Pathway; Signal Transduction; Syndrome; TLR2 gene; TLR4 gene; Testing; Tissues; Toll-Like Receptor 2; Toll-like receptors; Trauma; United States; Ventricular; attenuation; effective therapy; improved; mortality; novel; novel therapeutic intervention; pressure; prevent; public health relevance; receptor-mediated signaling; research study; response; septic

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.

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/或败血性休克。危重患者延迟死亡的一个主要原因是多器官功能障碍综合征（MODS）。目前的知识表明，MODS 与先天免疫失调有关，这可能涉及导致播散性组织损伤的高炎症休克状态，以及可能导致机会性感染的长期免疫抑制。脓毒症/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/脓毒性休克心功能障碍的病理生理学中发挥着核心作用。然而，先天免疫介导心脏功能障碍的机制现在才被人们所认识。此外，脓毒症/感染性休克中试图限制炎症反应、促进心肌细胞存活和维持心血管稳态的生理机制仍不清楚。 Toll 样受体 (TLR) 介导的信号传导在诱导先天反应和炎症反应中发挥着关键作用。我们的初步数据表明，TLR2 和 TLR4 在脓毒症/感染性休克期间对心脏功能具有显着不同和相反的影响，即差异性影响。我们的数据还表明，调节 TLR2/TLR4 依赖性信号通路可能是预防/管理脓毒症/感染性休克中心脏功能障碍的有效方法。本申请中概述的实验将检验以下假设：TLR2 和 TLR4 信号通路的差异调节决定心脏功能对脓毒症/脓毒性休克损伤的反应。为了检验这一假设，我们将追求三个具体目标。 1. 我们将阐明 TLR4 缺陷减轻脓毒症/脓毒性休克中心脏功能障碍的机制 2. 我们将定义调节 TLR2 改善脓毒症/脓毒性休克心脏功能的机制。 3.我们将研究TLR2/4和PI3K/Akt信号通路的差异调节是否对脓毒症/感染性休克期间的心脏保护具有附加作用。这些研究将为脓毒症中对心肌功能和/或功能障碍至关重要的信号通路提供机制上的理解。也有可能以实际方式应用这些知识来确定新的和新颖的治疗方法来预防或管理败血症/败血性休克中的心脏功能障碍。公共卫生相关性：危重患者经常会出现一系列复杂的疾病，其中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/或脓毒性休克以及多器官功能障碍综合征 (MODS)。在美国，每年约有 750,000 名患者出现脓毒症综合征。这些患者的总体死亡率为 28.6%（每年约 215,000 例死亡）。那些在最初的事件（可能包括创伤）中幸存下来的患者可能最终会死于广泛的器官功能障碍，这种功能障碍可能是由于过度炎症反应而导致的急性症状，也可能是由于免疫功能障碍和感染而导致的更长期的症状。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 发病率和死亡率相关。事实证明，开发针对败血症/败血性休克和 MODS 的有效疗法的尝试极其困难。这在一定程度上是由于我们对介导脓毒症心脏功能障碍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/脓毒性休克期间导致心脏功能障碍的分子机制对于开发可降低发病率和死亡率的辅助疗法至关重要。这些研究将提供对脓毒症心肌功能和/或功能障碍至关重要的细胞信号传导途径的机制理解。也有可能以实际方式应用这些知识来确定新的和新颖的治疗方法来预防或管理败血症/败血性休克中的心脏功能障碍。