The pathology of fibrotic lung diseases is characterized by fibroblastic foci in areas of active fibrosis. These fibroblastic foci contain fibroblasts with an activated, """"""""myofibroblast"""""""" phenotype. Myofibroblasts are key effector cells in the pathogenesis of pulmonary fibrosis due to their high protein synthetic capacity [extracellular matrix (ECM) proteins, integrins, growth factors, growth factor receptors], resistance to apoptosis, enhanced proliferative responses to mitogens and ability to generate extracellular oxidants. The pro-fibrotic cytokine, TGF- beta1, is a potent induces of myofibroblast both in-vivo and in-vitro. However, this differentiation signal induced by TGF-beta1 is dependent on cell adhesive events that have yet to be fully characterized. Myofibroblast differentiation is associated with the assembly/activation of a submembranous, adhesive, cytoskeletal complex that results in the generation of extracellular H2O2. We hypothesize that myofibroblast-derived H2O2mediates oxidative cross-linking of ECM proteins that alters the substratum for fibroblasts, promoting further myofibroblast differentiation and, thereby, resulting in a self-perpetuating, positive feedback loop, leading to an unrelenting fibrotic process.
Our specific aims are to: (1) Define signaling pathways that regulate myofibroblast differentiation: requirement for combinatorial signal integration of TGF-beta1 and cell adhesive signaling, (2) Characterize the H2O2-generating oxidase in myofibroblasts: association with focal adhesion and actin cytoskeleton, and (3) Examine physiologic/pathophysiologic effects of the myofibroblast- derived oxidants: role in oxidative cross-linking of ECM proteins. It is anticipated that completion of these studies will provide a better understanding of myofibroblast biology that will aid in the development of novel, targeted therapies for fibrotic diseases in which myofibroblasts play an active role including idiopathic pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL067967-02
Application #
6559919
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2001-10-01
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$280,886
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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