This is a competing continuation grant application that seeks to broaden current understanding of the biological role(s) of reactive oxygen species (ROS)-generating enzymes in myofibroblasts, key effector cells in tissue injury/repair processes. There is emerging evidence of an apoptosis-resistant phenotype of myofibroblasts, while alveolar epithelial cells undergo increased rates of apoptosis in lungs of patients with idiopathic pulmonary fibrosis (IPF). This """"""""apoptosis paradox"""""""" is likely perpetuated by paracrine and autocrine interactions between mesenchymal cells and epithelial cells. We have made the observation that the growth factor/morphogen, transforming growth factor-(1 (TGF-(1), generates extracellular hydrogen peroxide (H2O2) in contrast to intracellular ROS by classical mitogenic growth factors in lung myofibroblasts. The extracellular generation of H2O2 is mediated by the nicotinamide adenine dinucleotide (phosphate) [NAD(P)+;NAD(P)H, reduced form] oxidase, Nox4, a homolog of the phagocytic oxidase, gp91phox (or Nox2). Activation of Nox4 is associated with the induction of myofibroblast differentiation and survival in response to TGF-(1. In vivo targeting of Nox4 activity by pharmacologic or RNAi approaches attenuates injury-provoked lung fibrosis in a murine model. Our hypothesis is that the activation of Nox4-dependent H2O2 production by TGF-(1 regulates myofibroblast proliferation and/or survival. Further, we hypothesize that blockade of Nox4 activity in vivo protects against fibrogenic responses to lung injury.
Our specific aims are to: (1) determine mechanisms for Nox4 induction/activation by TGF-(1 in myofibroblasts and the role of Nox4/H2O2 in regulation of myofibroblast differentiation, proliferation and survival;(2) investigate the inherent heterogeneity of Nox4 expression/H2O2 production in IPF fibroblasts and determine relationship of Nox4 activity to specific myofibroblast phenotypes;(3) determine if inhibition/loss of NOX enzyme(s) in vivo protects against fibrosis in an experimental murine model of pulmonary fibrosis.

Public Health Relevance

. The lung is exposed to various forms of injury. Abnormal repair responses can lead to the persistent activation of myofibroblasts that culminate in matrix remodeling and fibrosis (""""""""scarring"""""""") leading to organ failure and death. Understanding mechanisms of lung repair and remodeling will provide novel targets for treatment of fibrotic lung disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067967-09
Application #
8082741
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2001-08-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2011
Total Cost
$362,693
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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