Control of Fibroblast Function by Prostaglandin E2 and Plasminogen Activation

描述(申请人提供)：特发性肺纤维化(IPF)是一种毁灭性的，通常是致命的疤痕疾病。肌成纤维细胞是这种疾病的关键效应细胞，具有丰富的细胞外基质蛋白，如构成组织瘢痕的胶原蛋白。新的研究表明，过度活跃的黏附/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。已证明IPF缺乏的两条抗纤维化途径是：1)脂质介导物前列腺素E2(PGE2)及其相关的G蛋白偶联受体和环磷酸腺苷(CAMP)效应物；2)蛋白水解级联反应，尿激酶将纤溶酶原转化为纤溶酶原。我们之前已经证明，这两个通路之间的串扰对于它们的抗纤维化功能至关重要。我们新的初步数据表明，PGE2通过cAMP和经典cAMP效应器蛋白激酶A的不同亚型，可以通过靶向抑制黏附信号和蛋白质翻译 各种关键检查站。此外，我们的数据表明，除了阻止肌成纤维细胞分化外，PGE2还可以将肌成纤维细胞的分化状态逆转为成纤维细胞；鉴于大多数患者的临床表现已经是晚期纤维化，这一点具有重要的治疗意义。这项建议的总体目标是：1)了解PGE2调节黏附信号和蛋白质翻译的机制；2)确定纤溶酶是否具有类似的作用，或者是否相反，它增强了PGE2的作用；3)确定破坏黏附信号和蛋白质翻译在PGE2逆转肌纤维母细胞分化能力中的重要性；以及4)评估吸入PGE2和/或尿激酶在两种肺纤维化模型中改善纤维化和逆转体内肌成纤维细胞分化的潜力。这些拟议的研究将为成纤维细胞生物学和翻译调控提供新的基础见解，并为IPF和其他纤维性肺部疾病的治疗提供潜在的新范式。

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.