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.
