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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL058795-06A1
Application #
6731289
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
1998-04-01
Project End
2009-01-31
Budget Start
2004-02-13
Budget End
2005-01-31
Support Year
6
Fiscal Year
2004
Total Cost
$363,680
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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