Departments of Pharmacology Medicine, University of California San Diego, La Jolla, CA 92093, USA.
Br J Pharmacol. 2012 May;166(2):447-56. doi: 10.1111/j.1476-5381.2012.01847.x.
Fibrosis, the result of excess deposition of extracellular matrix (ECM), in particular collagen, leads to scarring and loss of function in tissues that include the heart, lung, kidney and liver. The second messenger cAMP can inhibit the formation and extent of ECM during this late phase of inflammation, but the mechanisms for these actions of cAMP and of agents that elevate tissue cAMP levels are not well understood. In this article, we review the fibrotic process and focus on two recently recognized aspects of actions of cAMP and its effector Epac (Exchange protein activated by cAMP): (a) blunting of epithelial-mesenchymal transformation (EMT) and (b) down-regulation of Epac expression by profibrotic agents (e.g. TGF-β, angiotensin II), which may promote tissue fibrosis by decreasing Epac-mediated antifibrotic actions. Pharmacological approaches that raise cAMP or blunt the decrease in Epac expression by profibrotic agents may thus be strategies to block or perhaps reverse tissue fibrosis. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2.
纤维化是细胞外基质（ECM），特别是胶原蛋白过度沉积的结果，导致包括心脏、肺、肾和肝在内的组织瘢痕形成和功能丧失。第二信使 cAMP 可以抑制炎症晚期 ECM 的形成和程度，但 cAMP 的这些作用以及能提高组织 cAMP 水平的药物的作用机制尚不清楚。本文综述了纤维化过程，并重点介绍了 cAMP 及其效应物 Epac（cAMP 激活的交换蛋白）的两个最近被认识到的作用：（a）削弱上皮-间充质转化（EMT），（b）促纤维化剂（如 TGF-β、血管紧张素 II）下调 Epac 表达，这可能通过减少 Epac 介导的抗纤维化作用促进组织纤维化。因此，提高 cAMP 或阻止促纤维化剂降低 Epac 表达的药物方法可能是阻止或逆转组织纤维化的策略。
相关文章 本文是关于新型 cAMP 信号传导模式的专题部分的一部分。要查看该部分的其他文章，请访问 http://dx.doi.org/10.1111/bph.2012.166.issue-2。
