Control of Fibroblast Function by Prostaglandin E2 and Plasminogen Activation

描述（由申请人提供）：特发性肺纤维化（IPF）是一种毁灭性的，通常是致命的疤痕性疾病。这种疾病的关键效应细胞是肌成纤维细胞，具有丰富的细胞外基质蛋白（如构成组织瘢痕的胶原蛋白）的加工能力。新兴研究表明，过度活跃的粘附/僵硬信号和蛋白质翻译有助于肌成纤维细胞的分化和激活。对内源性抗纤维化途径的关注较少。IPF缺乏的两种抗纤维化途径是：1)脂质介质前列腺素E2 （PGE2）及其相关的G蛋白偶联受体和环AMP （cAMP）效应器，以及2)尿激酶将纤溶酶原转化为纤溶酶的蛋白水解级联。我们之前已经证明，这两种通路之间的串扰对它们的抗纤维化功能至关重要。我们的新初步数据表明，PGE2通过cAMP和经典cAMP效应蛋白激酶A的不同亚型，可以通过靶向抑制粘附信号和蛋白质翻译

DESCRIPTION (provided by applicant): 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.