Regulation of redox signaling by ceramide during pulmonary Pseudomonas aeruginosa infections
Recent studies using human subjects and animal studies using Cftr-deficient mice highlight a role of ceramide in the development of this inherited disease (Teichgräber et al., 2008; Becker et al., 2009; Yu et al., 2009; Brodlie et al., 2010). Particularly, our group has demonstrated that alteration in ceramide metabolism contributes to the pathological development of cystic fibrosis. Age-dependent accumulation of ceramide was detected in the epithelium of the lungs of Cftr-deficient mice. However, it is unknown whether ceramide is also altered in other lung cells. Alveolar macrophages serve as the first line of host defense to clear extracellular bacteria from the lung. These lung resident macrophages are critically involved in coordinating the innate immune response during the bacterial infection. At present, the role of alveolar macrophage in cystic fibrosis is not well understood. The present thesis first defines the role of ceramide-mediated signaling in regulating functions of lung alveolar macrophages during pulmonary P. aeruginosa infections. Because ceramide is an important signaling molecule that regulates redox signaling (Zhang et al., 2007), the present study will investigate whether P. aeruginosa infections result in activation of acid sphingomyelinase, formation of ceramide-enriched membrane platforms and clustering of NADPH oxidase in the plasma membrane. The importance of acid sphingomyelinase and ceramide platforms for NADPH oxidase-derived ROS production will be tested by using Acid sphingomyelinase-deficient cells. The second part of the study addresses whether Cftr-deficiency results in alterations of ceramide metabolism and ceramide-mediated redox signaling in lung alveolar macrophages. Because CFTR increases pH in at least some intracellular vesicles such as lysosomes by its action to mediate the influx of counterions into intracellular vesicles (Barasch et al., 1991; Poschet et al., 2002; Di et al., 2006; Teichgräber et al., 2008; Deriy et al., 2009). It will be tested whether Cftr-deficiency causes defects in lysosomal acidification, acid sphingomyelinase/ceramide-mediated amplification of redox signaling and killing invaded P. aeruginosa by these lung macrophages. Our results will increase the understanding of the signaling mechanisms that cause defects in innate responses of cystic fibrosis lungs and the high susceptibility to P. aeruginosa infections.
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