SURFACTANT METABOLISM IN PNEUMOCYSTIS CARINII PNEUMONIA

尽管最近在诊断、治疗和预防方面取得了进展， 卡氏肺孢子虫肺炎（PCP）仍然是发病的主要原因 艾滋病毒/艾滋病患者的死亡率 （艾滋病）。这种危及生命的机会性感染与 气体交换受损，导致临床上显著的低氧血症。的 疾病是由一种神秘的病原体引起的， 由于难以在体外培养生物体， 繁琐的感染动物模型。表面活性剂异常， 肺部炎症似乎在 PCP的发病机制及其相关的低氧血症;然而， 并且这些事件的效应器机制是未知的。因为 PCP引起的缺氧性肺损伤与 表面活性剂生物物理学和脂质含量，我们假设：（i）严重 直接引起正常肺表面活性物质稳态的破坏 P. carinii。卡氏肺孢子虫与远侧牙槽骨的相互作用 上皮由丰富的免疫原性细胞表面蛋白介导， 在生物体的细胞外壁上发现的糖蛋白A（gpA）。这些 事件包括表面活性剂脂质代谢的改变和 表面活性物质特异性蛋白的表达和细胞代谢。 (ii)通过TNF-α介导的其他间接机制， 宿主炎症反应进一步破坏了表面活性剂体内平衡。我们 建议描述gpA在特定相互作用中的作用， 这种有机体与宿主上皮细胞和研究机制， 肺孢子虫介导使用小鼠观察到的PCP严重肺损伤 感染的模式。具体目标是：（1）明确细胞效应 肺孢子虫gp-A对肺表面活性物质代谢的影响;（2） 表征免疫功能低下患者中表面活性剂代谢的变化 PCP小鼠模型。为了实现这些目标，我们将利用体内 动物系统生长卡氏肺孢子虫作为纯化gp-A的来源， PCP感染的控制模型。该项目将结合联合收割机元素 从几个专题研究项目中得出一个全面的 研究建议包括：1）一名主要研究者， 表面活性剂生物学主要领域的专业知识; 2）共同研究者 卡氏肺孢子虫生物学、gpA纯化和动物模型的经验 PCP; 3）公认的scid小鼠模型权威顾问 五氯酚这些研究的结果将进一步加深我们对 卡氏肺孢子虫肺部感染的发病机制。

Despite recent advances in its diagnosis, therapy, and prophylaxis, Pneumocystis carinii pneumonia (PCP) remains a leading cause of morbidity and mortality in patients with the Acquired Immunodeficiency Syndrome (AIDS). This life-threatening opportunistic infection is associated with impaired gas exchange leading to clinically significant hypoxemia. The disease is caused by an enigmatic pathogen whose basic biology is poorly understood because of difficulty culturing the organism in vitro and cumbersome animal models of the infection. Surfactant abnormalities and pulmonary inflammation appear to have an important role in the pathogenesis of PCP and its associated hypoxemia; however the initiating and effector mechanisms for these events are not known. Because the hypoxic lung injury produced by PCP is associated with abnormalities in surfactant biophysics and lipid content, we hypothesize that: (i) severe disruption of normal pulmonary surfactant homeostasis is induced directly by P. carinii. The interaction of P. carinii with the distal alveolar epithelium is mediated by an abundant, immunogenic, cell-surface protein, glycoprotein A (gpA) found on the outer cell wall of the organism. These events include alteration in surfactant lipid metabolism and changes in the expression and cellular metabolism of surfactant specific proteins. (ii) Additional indirect mechanisms mediated via TNF-alpha produced by the host inflammatory response further disrupt surfactant homeostasis. We propose to characterize the role of gpA in the specific interaction of this organism with host epithelial cells and study mechanisms by which Pneumocystis mediates the severe lung injury seen with PCP using a murine model of infection. The specific aims are: (1) Define the cellular effects of Pneumocystis gp-A on lung surfactant metabolism in vitro; (2) Characterize changes in surfactant metabolism in an immunocompromised mouse model of PCP. To accomplish these aims, we will utilize in vivo animal systems to grow P. carinii as a source of purified gp-A and a well- controlled model of PCP infection. The project will combine elements derived from several thematic research programs to yield a comprehensive investigative proposal including: 1) A Principal Investigator with expertise in the major areas of surfactant biology; 2) a co-investigator experiences with P. carinii biology, gpA purification and animal models of PCP; 3) A consultant recognized as an authority on the scid mouse model of PCP. Results from these studies will further our understanding of the pathogenesis of P. carinii lung infection.