C. pneumoniae and atherosclerotic plaque destabilization

肺炎衣原体(肺炎衣原体)感染与心血管风险增加相关 不稳定型心绞痛患者的发病率、死亡率和抗体滴度均升高。这个 肺炎衣原体抗体的流行率在老年人中也是最高的，这一人群患肺炎的风险最高 已确定的心血管疾病的死亡率。肺炎衣原体感染从肺部传播到 被感染的巨噬细胞造成的动脉壁。持续感染发生在血管内皮细胞、平滑肌 动脉粥样硬化斑块内的细胞和巨噬细胞，但很少在正常动脉内。我们和其他人， 已经证明肺炎衣原体感染会加速脂肪条纹的发展 高胆固醇血症动物模型。然而，到目前为止，关于肺炎衣原体是否 感染导致了疾病进程的晚期。此外，目前还不清楚是否 肺炎衣原体感染对肺上皮细胞和巨噬细胞的间接影响 病变进展或对晚期病变是否有任何影响需要直接感染血管细胞。在……里面 在这项提案中，我们将重点模拟肺炎衣原体对晚期肺炎的影响。 动脉硬化。此外，我们将跟踪观察到的Toll样受体-2在很大程度上介导 巨噬细胞对肺炎衣原体的反应。我们推测肺炎衣原体感染 巨噬细胞通过激活TLR-2参与晚期动脉粥样硬化病变的进展 直接或间接增强病变血管内正在进行的炎症反应。 炎症反应的增强反过来导致细胞死亡和血管扩张的增加 核心坏死，随后伤口愈合，纤维化转化，血管钙化增加。为了测试 在这些假说中，我们将追求以下具体目标：1.确定C. 肺炎杆菌诱导小鼠caspase非依赖性死亡并同时刺激三磷酸腺苷的产生 巨噬细胞。2.确定Toll样受体TLR-2和TLR-4的缺失以及 辅助蛋白MyD88改变急性期反应防止动脉粥样硬化加速 肺炎衣原体感染C57BI/6和Apo E-/-小鼠。3.确定肺炎衣原体是如何 巨噬细胞的感染在体外和体内均可导致血管钙化。4.确定是否 将幼年小鼠与老年小鼠暴露在空气污染中会增加小鼠对肺炎链球菌的易感性 感染并加速动脉粥样硬化的发展和进展。

Infection with Chlamydia pneumonias (C. pneumoniae) is associatedwith an increased risk of cardiovascular disease morbidity and mortality and antibody titers are elevated in those with unstable angina. The prevalence of C. pneumoniae antibodies is also highest in the elderly, the population at greatest risk of mortality from established cardiovascular disease. C. pneumoniae infection is disseminated from the lungs to the artery wall by infected macrophages. Sustained infection occurs in endothelial cells, smooth muscle cells, and macrophages within atherosclerotic plaques but rarely within normal arteries. We, and others, have demonstrated that C. pneumoniae infection accelerates the development of fatty streaks in hypercholesterolemic animal models. However, to date little is known about whether C. pneumoniae infection contributes to the advanced stages of the disease process. Furthermore, it is still unclear whether there are indirect effects of C. pneumoniae infection of epithelial cells and macrophages in the lungs on lesion progression or whether any effects on advanced lesions requires direct infection of vascular cells. In this proposal, we will focus on modeling the effects of C. pneumoniae on the advanced stages of atherosclerosis. In addition, we will follow-up on the observation that the toll-like receptor-2 largely mediates the responses of macrophages to C. pneumoniae. We hypothesize that C. pneumoniae infection of macrophages contributes via activation of TLR-2 to the progression of advanced atherosclerotic lesions by both directly and indirectly potentiating the ongoing inflammatory response within the diseased blood vessel. The potentitation of the inflammatory response in turn leads to increased cell death and expansion of the necrotic core followed by a wound healing fibrotic conversion and increased vascular calcification. To test these hypotheses we will pursue the following specific aims: 1. To determine the mechanisms by which C. pneumoniae induces a caspase independent death and concurrently stimulates production of ATP in mouse macrophages. 2. To determine whether the absence of toll-like receptors TLR-2 and TLR-4 and the accessory protein MyD88 alters the acute phase response and prevents the acceleration of atherosclerosis induced by C. pneumoniae infection in C57BI/6 and Apo E-/- mice. 3. To determine how C. pneumoniae infection of macrophages contributes to vascular calcification in vitro and in vivo. 4. To determine whether exposure of young versus old mice to air pollution increases the susceptibility of the mice to C. pneumoniae infection and accelerates the development and progression of atherosclerosis.