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.
Le Cras, Timothy D; Korfhagen, Thomas R; Davidson, Cynthia et al. (2010) Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Pathol 176:679-86 |
Deshmukh, Hitesh S; McLachlan, Anne; Atkinson, Jeffrey J et al. (2009) Matrix metalloproteinase-14 mediates a phenotypic shift in the airways to increase mucin production. Am J Respir Crit Care Med 180:834-45 |
Kramer, Elizabeth L; Mushaben, Elizabeth M; Pastura, Patricia A et al. (2009) Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice. Am J Respir Cell Mol Biol 41:415-25 |
Korfhagen, Thomas R; Le Cras, Timothy D; Davidson, Cynthia R et al. (2009) Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 41:562-72 |
Glasser, Stephan W; Witt, Teah L; Senft, Albert P et al. (2009) Surfactant protein C-deficient mice are susceptible to respiratory syncytial virus infection. Am J Physiol Lung Cell Mol Physiol 297:L64-72 |
Bein, Kiflai; Wesselkamper, Scott C; Liu, Xiangdong et al. (2009) Surfactant-associated protein B is critical to survival in nickel-induced injury in mice. Am J Respir Cell Mol Biol 41:226-36 |
Hardie, William D; Davidson, Cynthia; Ikegami, Machiko et al. (2008) EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-alpha-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 294:L1217-25 |
Glasser, Stephan W; Senft, Albert P; Whitsett, Jeffrey A et al. (2008) Macrophage dysfunction and susceptibility to pulmonary Pseudomonas aeruginosa infection in surfactant protein C-deficient mice. J Immunol 181:621-8 |
Berclaz, Pierre-Yves; Carey, Brenna; Fillipi, Marie-Dominique et al. (2007) GM-CSF regulates a PU.1-dependent transcriptional program determining the pulmonary response to LPS. Am J Respir Cell Mol Biol 36:114-21 |
Ikegami, Machiko; Scoville, Elizabeth A; Grant, Shawn et al. (2007) Surfactant protein-D and surfactant inhibit endotoxin-induced pulmonary inflammation. Chest 132:1447-54 |
Showing the most recent 10 out of 31 publications