Pulmonary inflammatory processes due to bacterial pneumonia impose a considerable clinical burden of morbidity and mortality in the US and other countries. A number of microbes considered as potential bioterrorist threats cause severe pulmonary inflammation. During the previous funding period, studies using transgenic mice, demonstrated that surfactant protein-A (SP-A) reduces inflammation caused by microbes and microbial products. Studies from patients with pneumonia or cystic fibrosis (CF) demonstrated reduced concentrations of SP-A suggesting that SP-A modulates the extent of microbial induced pulmonary inflammation. The goal of the present application is to determine mechanisms whereby SP-A regulates pulmonary inflammatory responses. Recent studies have demonstrated important roles for toll-like receptors (TLR) in inducing inflammatory responses. TLR4 is a major receptor for LPS and gram-negative bacteria. LPS binds to CD14 and LPS/CD14 interacts with MD-2/TLR4 forming a cell surface tripartite receptor complex that transduces intracellular signals leading to activation of cytokines and other inflammatory modulators. SP-A does not bind smooth forms of LPS but SP-A blocks smooth LPS induced cytokine production in vivo and in vitro. The lack of binding to smooth LPS suggests that SP-A cannot simply be sequestering LPS from interactions with the TLR complex. TLR4, CD14, and MD-2 RNA are present in alveolar macrophages and mouse lung epithelial cells supporting the central hypothesis that SP-A alters inflammatory responses in the lung by reducing smooth LPS signaling through TLR-4 components. This hypothesis will be tested using smooth LPS mediated induction of NF-kappaB in cell transfections or LPS and gram-negative infection in mouse models to complete the following aims: (1) The SP-A structures and LPS receptor components that functionally interact to cause SP-A inhibition of LPS mediated signaling will be identified in vitro; (2) Mechanisms by which SP-A inhibits LPS mediated signaling will be determined by testing if SP-A alters interactions between TLR4 components necessary for LPS signaling in vitro; and (3) Structural domains of SP-A required for SP-A inhibition of LPS or gram-negative bacterial mediated signaling in vivo will be identified. The present application seeks to identify novel mechanisms of SP-A regulation of pulmonary inflammatory responses with the goal of identifying novel approaches to reducing pulmonary inflammation.
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