Idiopathic pulmonary fibrosis (IPF) is a devastating and usually fatal scarring disease. A pivotal effector cell in this disorder is the myofibroblast, with an exuberant capacity for elaboration of extracellular matrix proteins such as collagen that comprise tissue scars. Emerging research suggests that overactive adhesion/stiffness signaling and protein translation contribute to myofibroblast differentiation and activation. Less attention has been paid to endogenous anti- fibrotic pathways. Two such anti-fibrotic pathways that have been shown to be deficient in IPF are 1) the lipid mediator prostaglandin E2 (PGE2) and its associated G protein-coupled receptors and cyclic AMP (cAMP) effectors, and 2) the proteolytic cascade by which urokinase converts plasminogen to plasmin. We have previously shown that cross-talk between these two pathways is critical for their anti-fibrotic functions. Our new preliminary data suggest that PGE2, via cAMP and distinct isoforms of the classical cAMP effector protein kinase A, can inhibit both adhesion signaling and protein translation by targeting a variety of critical checkpoints. Moreover, our data suggest that, in addition to preventing myofibroblast differentiation, PGE2 can reverse the differentiated state of myofibroblasts back to fibroblasts; this has important therapeutic implications in view of the fact that most patients hav already advanced fibrosis on clinical presentation. The overall objectives of this proposal are to 1) understand the mechanisms by which PGE2 regulates adhesion signaling and protein translation; 2) determine whether plasmin has similar effects or if it instead potentiates the effects of PGE2; 3) determine the importance of disrupting adhesion signaling and protein translation in the ability of PGE2 to reverse myofibroblast differentiation; and 4) evaluate the potential of inhaled PGE2 and/or urokinase to ameliorate fibrosis and to reverse myofibroblast differentiation in vivo in two mouse models of pulmonary fibrosis. The proposed studies will provide new fundamental insights into fibroblast biology as well as translational control, and a potential new paradigm for therapeutics in IPF and other fibrotic lung diseases.
Pulmonary fibrosis is a devastating scarring disease that typically results in respiratory failure and death. The lipid mediator prostaglandin E2 serves an important brake on the lung scarring capabilities of activated fibroblasts but its production is impaired in pulmonary fibrosis. In this proposal, we will determine how prostaglandin E2 inhibits and reverses activation of cultured fibroblast and test its capability to accomplish this in mouse models of this disorder.
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