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.
|Wettlaufer, Scott H; Scott, Jacob P; McEachin, Richard C et al. (2016) Reversal of the Transcriptome by Prostaglandin E2 during Myofibroblast Dedifferentiation. Am J Respir Cell Mol Biol 54:114-27|
|Gu, Hongmei; Fisher, Amanda J; Mickler, Elizabeth A et al. (2016) Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB J 30:2336-50|
|Zaslona, Zbigniew; Peters-Golden, Marc (2015) Prostanoids in Asthma and COPD: Actions, Dysregulation, and Therapeutic Opportunities. Chest 148:1300-6|
|Huang, Steven K; Scruggs, Anne M; McEachin, Richard C et al. (2014) Lung fibroblasts from patients with idiopathic pulmonary fibrosis exhibit genome-wide differences in DNA methylation compared to fibroblasts from nonfibrotic lung. PLoS One 9:e107055|
|Okunishi, Katsuhide; DeGraaf, Angela J; Zaslona, Zbigniew et al. (2014) Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions. FASEB J 28:56-66|
|Degraaf, Angela Juliette; ZasÅ‚ona, Zbigniew; Bourdonnay, Emilie et al. (2014) Prostaglandin E2 reduces Toll-like receptor 4 expression in alveolar macrophages by inhibition of translation. Am J Respir Cell Mol Biol 51:242-50|
|ZasÅ‚ona, Zbigniew; Okunishi, Katsuhide; Bourdonnay, Emilie et al. (2014) Prostaglandin Eâ‚‚ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. J Allergy Clin Immunol 133:379-87|
|ZasÅ‚ona, Zbigniew; Przybranowski, Sally; Wilke, Carol et al. (2014) Resident alveolar macrophages suppress, whereas recruited monocytes promote, allergic lung inflammation in murine models of asthma. J Immunol 193:4245-53|
|Penke, Loka R K; Huang, Steven K; White, Eric S et al. (2014) Prostaglandin E2 inhibits Î±-smooth muscle actin transcription during myofibroblast differentiation via distinct mechanisms of modulation of serum response factor and myocardin-related transcription factor-A. J Biol Chem 289:17151-62|
|Garrison, Garth; Huang, Steven K; Okunishi, Katsuhide et al. (2013) Reversal of myofibroblast differentiation by prostaglandin E(2). Am J Respir Cell Mol Biol 48:550-8|
Showing the most recent 10 out of 20 publications