Statins protect against adverse cardiac events during pneumonia

描述(由申请人提供)：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。在CAP住院期间，多达1/5的65岁老年人经历了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住院的人在感染后长达一年的时间内仍处于与心脏相关的猝死的高风险状态。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和感染性死亡的主要原因。在过去的研究中，我们已经确定在感染过程中释放的肺炎球菌细胞壁以依赖于血小板激活因子(PAFR)的方式损伤心肌细胞，抑制其收缩能力，并导致挑战小鼠的死亡。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的表达和阻断肺炎链球菌毒素肺炎溶孔的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在肺炎期间也将保护心肌细胞免受细胞壁和肺炎溶血素介导的损伤，并防止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肺炎链球菌附着和杀死血管内皮细胞的能力。此外，给予他汀类药物1周的小鼠在静脉注射纯化肺炎球菌细胞壁后，可预防心力衰竭和死亡。因此，实验证据表明，他汀类药物有很大的潜力用于治疗肺炎期间的不良心脏事件。严格测试他汀类药物在肺炎期间是否对心肌细胞功能有保护作用。我们将：目标1：确定他汀类药物对肺炎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在感染野生型和肺炎溶血素缺陷细菌时对心肌细胞损伤的影响，评估暴露于肺炎溶血素后的体内和体外心肌细胞功能，并检测心肌细胞caspase非依赖性凋亡，这是通常由肺炎溶血素触发的途径。目的2：确定他汀类药物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对心脏功能的影响，我们将确定他汀类药物对来自野生型和乙醇胺生长细菌的细胞壁的攻击，后者与PAFR不相互作用，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)住院的人因不良心脏事件而猝死的风险增加，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溶血素的攻击。这项提案的目的是测试他汀类药物是否能保护小鼠免受肺炎期间的心脏损害。

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.