Statins protect against adverse cardiac events during pneumonia

他汀类药物可预防肺炎期间的不良心脏事件

• 批准号: 8245700
• 负责人: Carlos J Orihuela
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245700
• 关键词: Affect; Age-Years; Apoptosis; Arrhythmia; Asses; Bacteria; Cardiac; Cardiac Myocytes; Cardiovascular system; Caspase; Cell Death; Cell Wall; Cells; Cessation of life; Communities; Congestive Heart Failure; Contracts; Critical Care; Data; Elderly; Ethanolamines; Event; Exposure to; Gene Expression; Genes; Goals; Heart; Heart Diseases; Heart failure; Hospitalization; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro; Incidence; Individual; Infection; Intravenous; Life; Lung; Lung diseases; Lytic; Mediating; Molecular; Mus; Myocardial Infarction; National Heart, Lung, and Blood Institute; Oral; Pathway interactions; Platelet Activating Factor; Pneumococcal Pneumonia; Pneumonia; Prevention; Publishing; Randomized Clinical Trials; Research; Resolution; Risk; Streptococcus pneumoniae; Streptococcus pneumoniae plY protein; Sudden Death; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxin; Vascular Endothelial Cell; antimicrobial; cell injury; cell type; experience; heart function; high risk; in vivo; killings; meetings; mortality; prevent; prophylactic; public health relevance; uptake

DESCRIPTION (provided by applicant): Individuals hospitalized for community-acquired pneumonia (CAP) are at increased risk for sudden death as a result of adverse cardiac events. During hospitalization for CAP up to 1/5 of individuals >65 years of age experience some form of adverse cardiac event including arrhythmias, congestive heart failure, or myocardial infarction. Following successful resolution of the infection, individuals hospitalized for CAP remain at high-risk for sudden cardiac-related death for up to 1 year post-infection. Thus events occurring during pneumonia either aggravate existing cardiovascular conditions or directly affect cardiac function. Streptococcus pneumoniae (the pneumococcus) is the leading cause of CAP and infectious-related death among the elderly (>65 years). In past studies, we have determined that pneumococcal cell wall released during infection damages cardiomyocytes in a Platelet activating factor (PAFr)-dependent manner, inhibiting their ability to contract and leading to death of challenged mice. Recently, we have determined that statins (i.e. HMG-CoA reductase inhibitors) protect lung cells from damage during pneumonia by inhibiting PAFr expression and blocking lytic pore-formation by the pneumococcal toxin pneumolysin. For this reason, we hypothesize that statin therapy will also protect cardiomyocytes from cell wall and pneumolysin mediated damage during pneumonia and prevent the occurrence of adverse cardiac events. In support of this hypothesis we have collected data showing that statins reduced the ability of live bacteria and S. pneumoniae components to adhere to and kill vascular endothelial cells. Furthermore, that mice administered statins for 1 week were protected against heart failure and death following intravenous challenge with purified pneumococcal cell wall. Thus experimental evidence suggests that statins have strong potential to be used as a therapeutic agent against adverse cardiac events during pneumonia. To rigorously test whether statins protect cardiomyocyte function during pneumonia. We will: Aim 1: Determine impact of statin therapy on pneumolysin-mediated cardiomyocyte damage. We will examine the effect of statins on cardiomyocyte damage during infection with wild type and pneumolysin deficient bacteria, asses cardiomyocyte function in vivo and ex vivo following exposure to pneumolysin, and examine cardiomyocyte caspase-independent apoptosis, the pathway normally triggered by pneumolysin. Aim 2: Determine the impact of statin therapy on cardiomyocyte cell wall uptake. We will determine the impact of statins on cardiomyocyte PAFr expression and cell wall uptake in vitro and vivo, we will determine the impact of statin therapy on heart function following challenge with cell wall collected from wild type and ethanolamine grown bacteria, the latter which does not interact with PAFr, we will determine the impact of cell wall and statins on cardiomyocyte gene expression. PUBLIC HEALTH RELEVANCE: Individuals hospitalized for community-acquired pneumonia (CAP) are at increased risk for sudden death as a result of adverse cardiac events that are in part the result of noxious agents released by bacteria during the infection. Our published data suggests that statins are capable of protecting host cells against Streptococcus pneumoniae cell wall and the toxin pneumolysin. The goal of this proposal is to test if statins protect mice against heart damage during pneumonia.

描述（由申请人提供）：因社区获得性肺炎（CAP）住院的个体因不良心脏事件而猝死的风险增加。在CAP住院期间，多达1/5的>65岁的个体经历某种形式的不良心脏事件，包括心律失常、充血性心力衰竭或心肌梗死。在感染成功解决后，因CAP住院的个体在感染后长达1年的时间内仍处于心脏相关猝死的高风险中。因此，肺炎期间发生的事件要么加重现有的心血管疾病，要么直接影响心脏功能。 肺炎链球菌（肺炎球菌）是老年人（>65岁）CAP和感染相关死亡的主要原因。在过去的研究中，我们已经确定，感染期间释放的肺炎球菌细胞壁以血小板活化因子（PAFr）依赖性方式损害心肌细胞，抑制其收缩能力并导致受攻击小鼠死亡。最近，我们已经确定他汀类药物（即HMG-CoA还原酶抑制剂）通过抑制PAFr表达和阻断肺炎球菌毒素肺炎球菌溶血素引起的溶解性孔形成来保护肺细胞免受肺炎期间的损伤。因此，我们假设他汀类药物治疗也可以保护心肌细胞免受肺炎期间细胞壁和肺炎球菌溶血素介导的损伤，并预防不良心脏事件的发生。为了支持这一假设，我们收集的数据表明，他汀类药物降低了活细菌和S。pneumoniae组分粘附并杀死血管内皮细胞。此外，给予他汀类药物1周的小鼠在用纯化的肺炎球菌细胞壁静脉内攻击后免受心力衰竭和死亡。因此，实验证据表明，他汀类药物具有很强的潜力，可用作治疗药物，对不良心脏事件在肺炎。严格测试他汀类药物是否保护肺炎期间的心肌细胞功能。我们将：目的1：确定他汀类药物治疗对肺炎链球菌溶血素介导的心肌细胞损伤的影响。我们将研究他汀类药物对野生型和肺炎球菌溶血素缺陷型细菌感染期间心肌细胞损伤的影响，评估暴露于肺炎球菌溶血素后体内和体外心肌细胞功能，并研究心肌细胞半胱天冬酶非依赖性凋亡，这一途径通常由肺炎球菌溶血素触发。目的2：确定他汀类药物治疗对心肌细胞壁摄取的影响。我们将确定他汀类药物在体外和体内对心肌细胞PAFr表达和细胞壁摄取的影响，我们将确定他汀类药物治疗在用从野生型和乙醇胺生长的细菌收集的细胞壁攻击后对心脏功能的影响，后者不与PAFr相互作用，我们将确定细胞壁和他汀类药物对心肌细胞基因表达的影响。 公共卫生相关性：因社区获得性肺炎（CAP）住院的个人因不良心脏事件而猝死的风险增加，而不良心脏事件的部分原因是感染期间细菌释放的有毒物质。我们发表的数据表明，他汀类药物能够保护宿主细胞免受肺炎链球菌细胞壁和毒素肺炎球菌溶血素的侵害。这项提案的目的是测试他汀类药物是否能保护小鼠在肺炎期间免受心脏损伤。