REGULATION OF PSEUDOMONAS INDUCED LUNG INFLAMMATION

肺部炎症是由感染引发和持续的，其机制还不完全清楚。促炎细胞因子、趋化因子和黏附分子以及产生它们的肺泡巨噬细胞和呼吸道上皮细胞也起作用，但它们的相对重要性可能因宿主和感染的性质而不同。在囊性纤维化(CF)患者中，肺部炎症通常在婴儿早期发展，然后发展，特别是在感染铜绿假单胞菌之后。CHR表达缺陷如何导致强烈和进行性的肺部炎症反应以及对铜绿假单胞菌难治性感染的易感性尚不清楚。对于呼吸道上皮在调节肺部炎症中所起的作用，缺乏了解的同时也缺乏相关信息。这反映了到目前为止还没有一种选择性和稳健的方法来测试呼吸道上皮的作用。同样，基于相关的人类数据和在一些啮齿动物模型上的结果，已经提出了肿瘤坏死因子在铜绿假单胞菌感染的肺部炎症反应中和在CF中的重要作用，但后来的研究得出了相互矛盾的结果。这一建议解决了一个普遍的假设，即肿瘤坏死因子与呼吸上皮细胞协同作用，调节肺部炎症和对铜绿假单胞菌的天然免疫，并且异常调节导致了CF中过度的肺部炎症。目的1)探讨肿瘤坏死因子受体缺陷小鼠对铜绿假单胞菌早期肺炎性反应增强的基础。假设：急性气溶胶感染铜绿假单胞菌后，中性粒细胞招募和细菌清除的选择性早期增加将是由于肺实质细胞的炎症反应改变；这将至少部分反映这些细胞的微生物模式识别受体的表达改变，该受体转导炎症信号以响应铜绿假单胞菌。目的通过选择性阻断肺上皮细胞内核因子-kappaB的激活，探讨气道上皮细胞在铜绿假单胞菌肺部炎症反应中的作用。假设：呼吸道上皮细胞在铜绿假单胞菌引起的急性肺部炎症中起重要作用。目的3)确定CFTR基因敲除小鼠肺部炎症的增加程度，如果是这样的话，这是否是肺固有的，部分是由于呼吸道上皮中核因子-kappaB的异常激活。假设：CFTRKO小鼠将出现过度的肺部炎症。这将反映肺固有的过程，并将平行并至少部分依赖于呼吸道上皮中核因子-kappaB的激活。

The mechanisms by which lung inflammation is initiated and perpetuated in response to infection are incompletely understood. Pro-inflammatory cytokines, chemokines and adhesion molecules contribute, as do alveolar macrophages and respiratory epithelial cells which produce them, but their relative importance may differ depending on the host and the nature of the infection. In patients with cystic fibrosis (CF), lung inflammation commonly develops in early infancy and then progresses, particularly following acquisition of infection with Pseudomonas aeruginosa. How the defect in CHR expression results in the intense and progressive lung inflammatory response and predisposition to refractory infection with P. aeruginosa is unclear. This lack of understanding parallels a paucity of information regarding the role which the respiratory epithelium plays in the regulation of lung inflammation in general. This reflects the absence heretofore of a selective and robust approach by which to test the contribution of the respiratory epithelium. Similarly, an important role for TNF in lung inflammation in response to infection with P. aeruginosa and in CF has been proposed based on correlative human data and results in some rodent models, but the latter studies have yielded contradictory results. This proposal addresses the general hypothesis that TNF acts in concert with the respiratory epithelium to regulate lung inflammation and innate immunity to Pseudomonas aeruginosa, and that aberrant regulation leads to excess lung inflammation in CF. Aim 1) Explore the basis for the increased early lung inflammatory response to P. aeruginosa in TNF receptor-deficient mice. Hypothesis: The selective early increase in neutrophil recruitment and bacterial clearance following acute aerosol infection with P. aeruginosa will be due to an altered inflammatory response by lung parenchymal cells; this will reflect, at least in part, altered expression by these cells of microbial pattern recognition receptors that transduce inflammatory signals in response to P. aeruginosa. Aim 2) Explore the role of the airway epithelium in the pulmonary inflammatory response to P. aeruginosa using mice in which NF-kappaB activation is blocked selectively and in a cell-autonomous fashion in the airway epithelium. Hypothesis: The airway epithelium will play an important role in initiating acute lung inflammation in response to P. aeruginosa. Aim 3) Determine the degree to which lung inflammation is increased in the lungs of CFTR knockout mice, and if so, if this is intrinsic to the lung and due in part to aberrant activation of NF-kappaB in the airway epithelium. Hypothesis: CFTR KO mice will have excessive lung inflammation. This will reflect a process intrinsic to the lung and will parallel and be dependent, at least in part, on NF-kappaB activation in the airway epithelium.