Amiodarone (AMD), an antiarrhythmic drug, is used cautiously due to its lung toxicity that is characterized by alveolar inflammation followed by fatal fibrosis. AMD induces lung inflammation via increasing the alveolar macrophages and disturbing the balance of T-helper-1 (Th1) and Th2 cells cytokines. In this study, the role of the mitogen-activated protein kinases (MAPKs)/activator protein-1 (AP-1) pathway in AMD-induced lung inflammation was evaluated. Also, the anti-inflammatory and antifibrotic effects of losartan and/or vitamin D were investigated following 7, 14, and 28 days of AMD administration. AMD resulted in lung injury, inflammatory infiltration, and increased pulmonary levels of inflammatory cytokines starting from Week 1 of exposure. A significant increase in serum levels of interleukin-4 along with a significant reduction of interferon-gamma, in addition to strong expression of CD68, were reported after 14 and 28 days of AMD administration reflecting Th1/Th2 cytokines imbalance and the accumulation of alveolar macrophages, respectively. The phosphorylation of MAPKs (ERK1/2, JNK, p38) and AP-1 was significantly enhanced starting from Week 1 of exposure. Marked expression of transforming growth factor beta-1 and massive deposition of collagen were detected after 28 days reflecting late fibrosis. All these abnormalities were significantly mitigated by vitamin D and its combination with losartan. Losartan alone has less prominent anti-inflammatory effects particularly after 28 days; however, it efficiently prevented late fibrosis. This study concludes that MAPKs/AP-1 pathway is involved in AMD-induced lung inflammation and that vitamin D and/or losartan could be used as a prophylactic agent to prevent AMD-induced lung toxicity.

中文翻译：

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氯沙坦和维生素D对胺碘酮诱导的大鼠肺部炎症的抑制机制：丝裂原活化蛋白激酶/激活蛋白-1的作用

胺碘酮 (AMD) 是一种抗心律失常药物，由于其肺部毒性，其特点是肺泡炎症，随后是致命的纤维化，因此被谨慎使用。AMD 通过增加肺泡巨噬细胞和扰乱 T-helper-1 (Th1) 和 Th2 细胞细胞因子的平衡来诱导肺部炎症。在这项研究中，评估了丝裂原活化蛋白激酶 (MAPKs)/激活蛋白-1 (AP-1) 通路在 AMD 诱导的肺部炎症中的作用。此外，在 AMD 给药 7、14 和 28 天后，研究了氯沙坦和/或维生素 D 的抗炎和抗纤维化作用。从暴露的第 1 周开始，AMD 导致肺损伤、炎症浸润和肺部炎症细胞因子水平升高。据报道，在 AMD 给药 14 天和 28 天后，除了 CD68 的强表达外，血清白介素 4 水平显着增加，干扰素 γ 显着降低，这反映了 Th1/Th2 细胞因子失衡和肺泡巨噬细胞的积累， 分别。MAPKs (ERK1/2, JNK, p38) 和 AP-1 的磷酸化从暴露的第 1 周开始显着增强。28 天后检测到转化生长因子 β-1 的显着表达和大量胶原沉积，反映了晚期纤维化。维生素 D 及其与氯沙坦的组合显着减轻了所有这些异常。单独使用氯沙坦的抗炎作用较不显着，尤其是在 28 天后；然而，它有效地预防了晚期纤维化。