Project 2 Project 2, """"""""Surfactant proteins in noninfectious inflammatory and fibroproliferative lung diseases"""""""", willtest the hypothesis that, in addition to playing important roles in modulating the host response toinfectious agents, SP-A and SP-D modulate the host response to noninfectious agents that causefibroproliferative disease by regulating the production, clearance and functions of endogenous hostfactors such as HA and by modulating the host cell responses to these factors. In collaboration withProject 1, our preliminary data show that, compared to wild type mice, SP-A and SP-D null mice haveenhanced susceptibility to bleomycin-induced pulmonary fibrosis, inflammation, fibrosis, and deathand that, in the absence of SP-A and SP-D, there is a marked increase in the accumulation of theextracellular matrix glycosaminoglycan hyaluronan (HA) as well as TGFbetal. Additionally, SP-A bindsHA and TGFbetal and regulates their functions and a deficiency of SP-A and SP-D in the bleomycintreated mice results in an invasive fibroblast phenotype that we speculate contributes to the fibrosisand injury. In collaboration with Project 3 (Kraft) using an ovalbumin model of In another model offibroproliferative lung injury in collaboration with Project 3 (Kraft), ovalbumin induced allergic ainwaydisease, SP-A null mice have elevated inflammation, TH2 skewing, and increased airway reactivitycompared to wild type mice.
Three aims will be addressed.
The first aim will focus on delineating therole of HA fragment accumulation in the exuberant inflammatory and fibrotic phenotype obsen/ed inSP-A and SP-D mice in response to bleomycin.
Aim 2 will focus on the interesting observation that inthe absence of SP-A and SP-D, there appears to be increased activity of TGFbetal.
The third aim willinvestigate both the source of the invasive fibroblast phenotype in the absence of SP-A and SP-D andthe role of HA and CD44 in the development of the phenotype in both bleomcyin-induced fibrosis andchronic allergen-induced ainway remodeling. These studies will provide insights into the linksbetween the innate immune system, matrix turnover and fibroproliferative lung diseases.

Public Health Relevance

These studies, which link closely with Project 1 (Noble) and 2 (Kraft), will investigate a novel concept that SP-A and SP-D play important roles in noninfectious lung injury via their ability to act asantagonists to HA and TGFB mediated lung injury. They will contribute to our understanding of the potential for surfactant protein therapy to be beneficial in the treatment of acute exacerbations of pulmonary fibrosis and asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-CSR-S)
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Cedars-Sinai Medical Center
Los Angeles
United States
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