REGULATION OF PSEUDOMONAS INDUCED LUNG INFLAMMATION

肺部炎症在感染反应中引发和延续的机制尚不完全清楚。促炎细胞因子、趋化因子和粘附分子，肺泡巨噬细胞和产生它们的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异。在囊性纤维化（CF）患者中，肺部炎症通常在婴儿期早期发生，然后发展，特别是在获得铜绿假单胞菌感染后。CHR表达缺陷是如何导致肺部强烈和进行性炎症反应以及铜绿假单胞菌难愈感染的易感性尚不清楚。这种理解的缺乏与关于呼吸上皮在肺炎症的一般调节中所起作用的信息的缺乏是一致的。这反映了迄今为止缺乏一种选择性和稳健的方法来测试呼吸上皮的贡献。同样，基于相关的人类数据和一些啮齿动物模型的结果，TNF在铜绿假单胞菌感染后的肺部炎症反应和CF中也发挥了重要作用，但后者的研究得出了相互矛盾的结果。本研究提出了一个普遍的假设，即TNF与呼吸道上皮协同作用，调节肺部炎症和对铜绿假单胞菌的先天免疫，而异常的调节导致CF中肺部过度炎症。目的1)探索TNF受体缺陷小鼠早期肺部对铜绿假单胞菌炎症反应增加的基础。假设：急性气溶胶感染铜绿假单胞菌后，中性粒细胞募集和细菌清除率的选择性早期增加可能是由于肺实质细胞炎症反应的改变；这至少在一定程度上反映了这些细胞的微生物模式识别受体的表达改变，这些受体在对铜绿假单胞菌的反应中转导炎症信号。目的2)利用选择性阻断NF-kappaB在气道上皮中以细胞自主方式激活的小鼠，探索气道上皮在铜绿假单胞菌肺部炎症反应中的作用。假设：气道上皮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增加的程度，如果是，如果这是肺部固有的，部分原因是气道上皮中NF-kappaB的异常激活。假设：CFTR KO小鼠会出现过度的肺部炎症。这反映了肺固有的一个过程，并且至少部分地平行并依赖于气道上皮中NF-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.