RESPIRATORY FAILURE IN A MODEL OF P. CARINII PNEUMONIA

描述（来自申请人摘要）：假设感染 卡氏肺孢子虫使肺泡上皮更容易受到继发性 损伤，特别是高氧，导致患者呼吸衰竭 用PCP为了评估这一假设，研究人员将利用一个 一种建立良好的CD 4耗尽的卡氏肺孢子虫肺炎小鼠模型， 随后暴露于高氧作为肺泡壁的典型应力 损伤他们提出，卡氏肺孢子虫感染的小鼠会发展得更严重， 暴露于高氧后的肺损伤。他们还假设GM-CSF， 由肺泡上皮细胞和巨噬细胞产生的强效细胞因子， 关键在于改善这种反应。应答诱导的GM-CSF表达 对卡氏肺孢子虫感染具有保护作用，以限制肺损伤。他们 假设高氧导致的肺GM-CSF表达的抑制， 这是一种促进肺损伤和呼吸衰竭的严重事件。四个具体 目标将得到实现。首先，他们将描述P的反应。 卡氏杆菌感染小鼠高氧。接下来，他们将确定表达式 在这种动物感染模型和遗传缺乏GM-CSF的小鼠中， 接触五氯苯酚和高氧条件后的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 GM-CSF对卡氏肺孢子虫肺炎及继发性肺炎保护作用 高氧后肺损伤的进展。

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.