Lung Damage from P. carinii: pathogenesis and prevention

描述（由申请人提供）： 卡氏肺孢子虫肺炎（PcP）是免疫系统受损患者（如AIDS患者或因恶性肿瘤、器官移植或其他潜在疾病接受免疫抑制治疗的患者）发病和死亡的重要原因。 这项拟议的计划项目资助（PPG）的中心假设是：PcP期间的肺损伤主要是对卡氏肺孢子虫免疫介导的炎症反应的结果，并且这种反应的特异性和有效控制将改善与PcP相关的发病率和死亡率。 为了在PcP小鼠模型中测试我们的假设，我们为该提议的PPG设定了以下目标： 1)阐明淋巴细胞、吞噬细胞和相关可溶性介质相互作用损伤肺泡上皮细胞、扰乱表面活性物质系统和干扰正常肺功能的机制。 2)利用通过完成目标1获得的知识，基于对特定损伤性炎症途径的控制，鉴定和测试潜在的新的PcP连续治疗。 为了实现我们的目标，我们组建了一个多学科的研究小组，他们将微生物学，免疫学，分子生物学，表面活性剂生物化学和生物物理学以及呼吸细胞和分子生物学的专业知识带到这个项目中。 这组研究人员将能够检查PcP的发病机制，从卡氏肺孢子虫和免疫系统的特定细胞之间的最初相互作用，通过卡氏肺孢子虫特异性免疫应答的发展，然后到肺泡上皮细胞和表面活性剂的影响，最终导致终末期肺功能障碍。 这项研究工作将确定潜在的治疗干预，以减少与PcP相关的发病率和死亡率的网站。 我

DESCRIPTION (provided by applicant): Pneumocystis carinii pneumonia (PcP) is a significant cause of morbidity and mortality in patients with a compromised immune system such as those with AIDS or those receiving immunosuppressive therapy for malignancy, organ transplantation or other underlying medical conditions. The central hypothesis for this proposed program project grant (PPG) is: lung injury during PcP is largely the result of the immune-mediated inflammatory response to P. carinii and that specific and effective control of this response will improve the morbidity and mortality associated with PcP. To test our hypothesis in mouse models of PcP we have set the following goals for this proposed PPG: 1) To elucidate the mechanisms by which lymphocytes, phagocytic cells and relevant soluble mediators interact to damage alveolar epithelial cells, perturb the surfactant system and interfere with normal lung function. 2) to utilize the knowledge gained through the completion of goal 1 to identify and test potential new adjunctive therapies for PcP based on control of specific injurious inflammatory pathways. To accomplish our goals we have assembled a multi-disciplinary group of investigators who bring expertise in microbiology, immunology, molecular biology, surfactant biochemistry and biophysics and respiratory cell and molecular biology to this project. This group of investigators will be able to examine the pathogenesis of PcP from the initial interaction between P. carinii and specific cells of the immune system through the development of a P. carinii-specific immune response then on to the effects of alveolar epithelial cells and surfactant with resultant end stage pulmonary dysfunction. This investigative effort will identify potential sites for therapeutic intervention to reduce the morbidity and mortality associated with PcP. I