C. pneumoniae and atherosclerotic plaque destabilization

肺炎衣原体感染（C。肺炎）与心血管疾病风险增加相关 不稳定型心绞痛患者的发病率和死亡率以及抗体滴度升高。的 C.流行肺炎抗体在老年人中也是最高的，老年人是肺炎风险最大的人群。 确诊心血管疾病的死亡率。C.肺炎感染是从肺部传播到 被感染的巨噬细胞破坏了动脉壁持续感染发生在内皮细胞、平滑肌 细胞和巨噬细胞，但很少在正常动脉内。我们和其他人， 证明了C.肺炎感染加速了脂肪条纹的发展， 高胆固醇血症动物模型。然而，到目前为止，很少有人知道是否C。肺炎 感染导致疾病进程的晚期。此外，尚不清楚是否 C.存在间接效应。肺炎感染的上皮细胞和巨噬细胞在肺上 病变进展或对晚期病变的任何影响是否需要直接感染血管细胞。在 这个建议，我们将集中在模拟C的影响。肺炎晚期 动脉粥样硬化此外，我们将继续观察Toll样受体-2在很大程度上介导 巨噬细胞对C.肺炎。我们假设C.肺炎感染 巨噬细胞通过激活TLR-2促进晚期动脉粥样硬化病变的进展， 直接和间接地增强患病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增加和炎症细胞的扩张。 坏死核心随后是伤口愈合纤维化转化和血管钙化增加。测试 这些假设，我们将追求以下具体目标：1。探讨C. 肺炎克雷伯菌诱导小鼠caspase非依赖性死亡并同时刺激ATP产生 巨噬细胞2.为了确定Toll样受体TLR-2和TLR-4的缺失以及Toll样受体的表达是否与Toll样受体的表达有关， 辅助蛋白MyD 88改变急性期反应并防止动脉粥样硬化的加速 诱导的C.在C57 B1/6和Apo E-/-小鼠中，3.确定C.肺炎 巨噬细胞的感染有助于体外和体内血管钙化。4.以确定是否 年轻小鼠与老年小鼠暴露于空气污染增加了小鼠对C.肺炎 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.