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Control of myofibroblast activation and pulmonary fibrosis by Na/K-ATPase

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? DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease characterized by parenchymal fibrosis and structural distortion of the lungs. There is no effective treatment for IPF and novel targets of pharmacologic intervention need to be identified. The pathogenesis of IPF is characterized by disordered and non-resolving wound healing. Injury of the alveolar epithelial cells results in the elaboration of various pro-inflammatory and pro-fibrotic mediators, of which Transforming Growth Factor-? (TGF-?) is the most established. Under stimulation with TGF-?, alveolar fibroblasts differentiate into myofibroblasts, by de novo expression of smooth muscle-specific contractile proteins, and secretion of extracellular matrix proteins and of pro-fibrotic, survival and growth factors. These myofibroblasts are invariably found on histological sections of lung specimens from patients with pulmonary fibrosis and are believed to play an important role in the pathogenesis of this disease. Therefore, targeting myofibroblast differentiation and growth/survival could be an attractive therapeutic strategy for prevention/treatment of pulmonary fibrosis. Na/K-ATPase (sodium pump) is an enzyme that pumps 3Na+ out of the cell and 2K+ into the cell against their gradient, and thus plays a key role in the maintenance of electrochemical gradients of monovalent cations and of electrical potential in various cells. Cardiac glycosides such as digoxin or ouabain that inhibit Na/K- ATPase have been used for treatment of heart diseases for decades. Our new findings suggest a novel role of Na/K-ATPase in a control of myofibroblast differentiation and pulmonary fibrosis and suggest a new therapeutic potential of cardiac glycosides. Based on our preliminary data, we hypothesize that (i) the activity of Na/K-ATPase is required for myofibroblast activation in response to TGF-?, (ii) inhibition of Na/K-ATPase by cardiac glycosides leads to attenuated myofibroblast activation in vitro through a novel dual mechanism involving downregulation of TGF-? receptor-2 expression and induction of cyclooxygenase-2 expression, and (iii) cardiac glycosides may have a protective effect at low doses in mouse models of pulmonary fibrosis. To test these hypotheses, we propose three specific aims: (i) examine the regulation of myofibroblast activation through inhibition of Na+/K+-ATPase and the mechanisms of this effect in human lung fibroblasts, (ii) examine the potential protective effect of digoxin on the severity of pulmonary fibrosis in mouse models, and (iii) examine the anti-fibrotic effect of other cardiotonic steroids in vitro and in vivo.
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