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(如艾滋病患者或因恶性肿瘤、器官移植或其他潜在疾病而接受免疫抑制治疗的患者)发病率和死亡率的重要原因。这项拟议的项目拨款(PPG)的中心假设是：PCP期间的肺损伤在很大程度上是对卡氏肺孢子虫的免疫介导性炎症反应的结果，对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的小鼠模型上测试我们的假设，我们为这个拟议的PPG设定了以下目标： 1)阐明淋巴细胞、吞噬细胞及相关的可溶性介质相互作用损伤肺泡上皮细胞、扰乱肺表面活性物质系统、干扰正常肺功能的机制。 2)利用通过完成目标1而获得的知识，基于对特定损伤性炎症途径的控制，识别和测试潜在的PCP新辅助治疗方法。 为了实现我们的目标，我们组建了一个多学科的研究小组，他们为这个项目带来了微生物学、免疫学、分子生物学、表面活性物质生物化学和生物物理学以及呼吸细胞和分子生物学方面的专业知识。这组研究人员将能够从卡氏肺孢子虫与免疫系统特定细胞之间的初始相互作用，通过发展卡氏肺孢子虫特异的免疫反应，然后到肺泡上皮细胞和表面活性物质的作用，从而导致终末期肺功能障碍，来研究PCP的发病机制。这项调查工作将确定潜在的治疗干预地点，以降低与PCP相关的发病率和死亡率。 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