Limb remote ischemic preconditioning (RIPC) is an effective means of protection against ischemia/reperfusion (IR)–induced injury to multiple organs. Many studies are focused on identifying endocrine mechanisms that underlie the cross-talk between muscle and RIPC-mediated organ protection. We report that RIPC releases irisin, a myokine derived from the extracellular portion of fibronectin domain–containing 5 protein (FNDC5) in skeletal muscle, to protect against injury to the lung. Human patients with neonatal respiratory distress syndrome show reduced concentrations of irisin in the serum and increased irisin concentrations in the bronchoalveolar lavage fluid, suggesting transfer of irisin from circulation to the lung under physiologic stress. In mice, application of brief periods of ischemia preconditioning stimulates release of irisin into circulation and transfer of irisin to the lung subjected to IR injury. Irisin, via lipid raft–mediated endocytosis, enters alveolar cells and targets mitochondria. Interaction between irisin and mitochondrial uncoupling protein 2 (UCP2) allows for prevention of IR-induced oxidative stress and preservation of mitochondrial function. Animal model studies show that intravenous administration of exogenous irisin protects against IR-induced injury to the lung via improvement of mitochondrial function, whereas in UCP2-deficient mice or in the presence of a UCP2 inhibitor, the protective effect of irisin is compromised. These results demonstrate that irisin is a myokine that facilitates RIPC-mediated lung protection. Targeting the action of irisin in mitochondria presents a potential therapeutic intervention for pulmonary IR injury.

肢体远端缺血预处理（RIPC）是防止缺血/再灌注（IR）引起的多器官损伤的有效手段。许多研究着重于确定内分泌机制，这些机制是肌肉与RIPC介导的器官保护之间相互影响的基础。我们报告说，RIPC释放虹膜素（肌动蛋白），肌动蛋白来自骨骼肌中含有5个蛋白（FNDC5）的纤连蛋白结构域的细胞外部分，以保护肺部免受伤害。患有新生儿呼吸窘迫综合征的人类患者显示血清中的鸢尾素浓度降低，而支气管肺泡灌洗液中的鸢尾素浓度升高，这表明在生理压力下，鸢尾素从循环系统转移到肺部。在老鼠中 短暂缺血预处理的应用会刺激虹膜素释放到循环系统中，并将虹膜素转移到遭受IR损伤的肺部。Irisin通过脂筏介导的内吞作用进入肺泡细胞并靶向线粒体。虹膜素与线粒体解偶联蛋白2（UCP2）之间的相互作用可防止IR诱导的氧化应激并保持线粒体功能。动物模型研究表明，外源性虹膜素的静脉内给药可通过改善线粒体功能来防止IR诱导的肺损伤，而在缺乏UCP2的小鼠中或存在UCP2抑制剂的情况下，虹膜素的保护作用会受到损害。这些结果表明，虹膜素是促进RIPC介导的肺保护的肌动蛋白。