The JAK-STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction
The JAK-STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction
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DOI：
10.2119/molmed.2014.00049
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发表时间：
2014-07-01
影响因子：
5.7
通讯作者：
Shrager, Joseph B.
中科院分区：
文献类型：
--
作者：
Tang, Huibin;Smith, Ira J.;Shrager, Joseph B.
机械通气（MV）是现代重症监护医学的关键之一，可以挽救许多危重患者的生命。然而，持续的呼吸机支持会导致通气诱导的膈肌功能障碍（VIDD），这可能会使患者对MV的需求减少，从而导致主要的相关并发症和可避免的重症监护室（ICU）死亡。氧化应激是VIDD发展中的关键致病事件，但其调节在很大程度上仍不明确。我们在这里报告，JAK-STAT途径被激活的MV在人类隔膜，证明了显着增加磷酸化的JAK和STAT。在大鼠MV模型中通过JAK抑制剂阻断JAK-STAT途径防止了膈肌收缩功能障碍（类似于85%，p < 0.01）。我们进一步证明，激活的STAT 3损害线粒体功能，并诱导体内氧化应激，有趣的是，氧化应激也激活JAK-STAT。抑制JAK-STAT可防止氧化应激诱导的蛋白质氧化和多聚泛素化，并恢复培养的肌细胞中的线粒体功能。因此，在通气的膈肌中，JAK-STAT的激活在调节氧化应激中是至关重要的，因此是临床VIDD下游发病机制的核心。这些发现为JAK-STAT抑制剂在ICU通气患者中的治疗前景奠定了分子基础。
Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK-STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK-STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by similar to 85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK-STAT. Inhibition of JAK-STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK-STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK-STAT inhibitors in ventilated ICU patients.