Department of Molecular Pathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstrasse 8, Tübingen, Germany.
Basic Res Cardiol. 2012 Sep;107(5):287. doi: 10.1007/s00395-012-0287-z. Epub 2012 Jul 27.
Enteroviruses, such as coxsackieviruses of group B (CVB), are able to induce a chronic inflammation of the myocardium, which may finally lead to the loss of functional tissue, remodeling processes and the development of fibrosis, thus affecting the proper contractile function of the heart. In other fibrotic diseases like scleroderma, the prostacyclin agonist iloprost was found to inhibit the extracellular signal-regulated kinase (ERK, p44/42 MAPK), a mitogen-activated protein kinase, and consecutively, the expression of the profibrotic cytokine connective tissue growth factor (CTGF), thereby preventing the development of fibrosis. As CTGF was found to mediate fibrosis in chronic CVB3 myocarditis as well, we evaluated whether the in vivo application of iloprost is capable to reduce the development of ERK/CTGF-mediated fibrosis in enteroviral myocarditis. Unexpectedly, the application of iloprost resulted in a prolonged myocardial inflammation and an aggravated fibrosis and failed to reduce activation of ERK and expression of CTGF at later stages of the disease. In addition, viral replication was found to be increased in iloprost-treated mice. Notably, the expression of cardiac inducible nitric oxide synthase (iNOS), which is known to aggravate myocardial damage in CVB3-infected mice, was strongly enhanced by iloprost. Using cultivated bone marrow macrophages (BMM), we confirmed these results, proving that iloprost potentiates the expression of iNOS mRNA and protein in CVB3-infected and IFN-gamma stimulated BMM. In conclusion, these results suggest a critical reflection of the clinical use of iloprost, especially in patients possibly suffering from an enteroviral myocarditis.
肠道病毒，如 B 组柯萨奇病毒（CVB），能够诱导心肌的慢性炎症，最终导致功能性组织丧失、重塑过程和纤维化的发展，从而影响心脏的正常收缩功能。在其他纤维化疾病中，如硬皮病，发现前列环素激动剂伊洛前列素能够抑制细胞外信号调节激酶（ERK，p44/42 MAPK），一种丝裂原激活蛋白激酶，从而抑制促纤维化细胞因子结缔组织生长因子（CTGF）的表达，从而防止纤维化的发展。由于 CTGF 被发现介导慢性 CVB3 心肌炎中的纤维化，我们评估了伊洛前列素在体内应用是否能够减少 ERK/CTGF 介导的心肌炎纤维化的发展。出乎意料的是，伊洛前列素的应用导致心肌炎症延长，纤维化加重，并且未能在疾病的后期阶段减少 ERK 的激活和 CTGF 的表达。此外，在接受伊洛前列素治疗的小鼠中发现病毒复制增加。值得注意的是，已知在 CVB3 感染的小鼠中加重心肌损伤的心脏诱导型一氧化氮合酶（iNOS）的表达被伊洛前列素强烈增强。使用培养的骨髓巨噬细胞（BMM），我们证实了这些结果，证明伊洛前列素增强了 CVB3 感染和 IFN-γ刺激的 BMM 中 iNOS mRNA 和蛋白的表达。总之，这些结果表明需要对伊洛前列素的临床应用进行批判性反思，特别是在可能患有肠道病毒心肌炎的患者中。
