RESPIRATORY FAILURE IN A MODEL OF P. CARINII PNEUMONIA

描述(摘自申请人的摘要)：假设感染了 卡氏肺孢子虫使肺泡上皮更容易发生继发性肺炎 侮辱，特别是高氧血症，会导致患者呼吸衰竭 使用五氯苯酚。为了评估这一假设，研究人员将利用 已建立的卡氏肺孢子虫肺炎的CD4耗竭小鼠模型 随后暴露在高氧环境中作为典型的肺泡壁应激 受伤。他们提出，感染卡氏肺孢子虫的小鼠将发展成更严重的 暴露在高氧环境下的肺损伤。他们还假设GM-CSF是一种 肺泡上皮细胞和巨噬细胞产生的强大细胞因子是 在改善这一反应方面至关重要。在应答中诱导GM-CSF表达 对卡氏肺孢子虫感染起到保护作用，限制肺损伤。他们 假设高氧对肺GM-CSF表达的抑制 导致肺损伤和呼吸衰竭的危重事件。四个具体的 AIMS将被实施。最初，他们将描述P。 卡氏肺吸虫感染高氧小鼠。接下来，他们将确定表达式 GM-CSF在该动物感染模型和遗传缺乏的小鼠中的表达 暴露于五氯酚和高氧条件下的GM-CSF。他们将进一步 确定卡氏肺孢子虫与肺泡上皮细胞的直接相互作用 细胞通过整合素诱导GM-CSF表达。最后，他们将评估 粒-巨噬细胞集落刺激因子在卡氏肺孢子虫肺炎及继发肺炎中的保护作用 高氧性肺损伤的进展。

DESCRIPTION (from applicant's abstract): It is hypothesized that infection with P. carinii renders the alveolar epithelium more susceptible to secondary insults, particularly hyperoxia, leading to respiratory failure in patients with PCP. To evaluate this hypothesis, the investigators will utilize a well-established CD4 depleted mouse model of P. carinii pneumonia, which is subsequently exposed to hyperoxia as a prototypical stress for alveolar wall injury. They propose that P. carinii infected mice will develop more severe lung injury following exposure to hyperoxia. They also postulate that GM-CSF, a potent cytokine generated by alveolar epithelial cells and macrophages, is critical in ameliorating this response. GM-CSF expression induced in response to P. carinii infection exerts a protective effect to limit lung injury. They postulate that inhibition of lung GM-CSF expression as a result of hyperoxia is a critical event promoting lung injury and respiratory failure. Four specific aims will be undertaken. Initially they will characterize the response of P. carinii infected mice to hyperoxia. Next, they will determine the expression of GM-CSF in this animal infection model and in mice that genetically lack GM-CSF following exposure to PCP and hyperoxic conditions. They will further determine whether direct interaction of P. carinii and alveolar epithelial cells through integrins induces GM-CSF expression. Finally, they will evaluate the protective effect of GM-CSF in P. carinii pneumonia and in subsequent progression of lung injury following hyperoxia.