This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Myofibroblasts are necessary cells for tissue remodeling and repair. The fact that, under certain circumstances, myofibroblasts persist and continue to secrete extracellular matrix has implicated them in interstitial fibrosis of the lung. Several studies suggest that nitric oxide (NO)-mediated signals may be important in regulating myofibroblast phenotypes. Inhibition of NO production leads to increased accumulation of myofibroblasts;NO reduces myofibroblast accumulation and collagen deposition;and transforming growth factor ? (TGF?), a known activator of myofibroblast differentiation, blocks myofibroblast apoptosis. In vivo, endothelial NOS (eNOS) knockout mice experience prolonged pulmonary fibrosis in response to the profibrotic agent bleomycin, suggesting that eNOS operates in regulating myofibroblast proliferation and/or apoptosis. The fact that the eNOS gene promoter can be induced by the mechanical force of laminar flow in epithelial cells, and the observation that other genes, ? smooth muscle actin (ASMA) in particular, are mechanotranscriptionally regulated in myofibroblasts, suggests a potential mechanism for regulating the expression of eNOS and thus apoptosis, in myofibroblasts. Therefore, we hypothesize that contraction of myofibroblasts mediates their apoptosis via eNOS signaling. In our current proposal, we are investigating three specific aims to extend our knowledge of the role of mechanical stress and NO in regulating myofibroblasts. One, we are evaluating the role of mechanical stress on pulmonary myofibroblast eNOS expression;two, we are determining the role of NO on pulmonary myofibroblast apoptosis;and three, we are assessing the deletion of sarcomeric myosin on bleomycin induced pulmonary fibrosis in vivo.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-4 (01))
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University of Louisville
Anatomy/Cell Biology
Schools of Medicine
United States
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