Rigel Pharmaceuticals, South San Francisco, California, USA; and.
Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
FASEB J. 2014 Jul;28(7):2790-803. doi: 10.1096/fj.13-244210. Epub 2014 Mar 26.
Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, and respiratory muscle weakness is thought to contribute significantly to delayed weaning of patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim of the current study was to investigate the role of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in CMV-mediated diaphragm wasting and weakness in rats. CMV-induced diaphragm atrophy and contractile dysfunction coincided with marked increases in STAT3 phosphorylation on both tyrosine 705 (Tyr705) and serine 727 (Ser727). STAT3 activation was accompanied by its translocation into mitochondria within diaphragm muscle and mitochondrial dysfunction. Inhibition of JAK signaling during CMV prevented phosphorylation of both target sites on STAT3, eliminated the accumulation of phosphorylated STAT3 within the mitochondria, and reversed the pathologic alterations in mitochondrial function, reduced oxidative stress in the diaphragm, and maintained normal diaphragm contractility. In addition, JAK inhibition during CMV blunted the activation of key proteolytic pathways in the diaphragm, as well as diaphragm atrophy. These findings implicate JAK/STAT3 signaling in the development of diaphragm muscle atrophy and dysfunction during CMV and suggest that the delayed extubation times associated with CMV can be prevented by inhibition of Janus kinase signaling.-Smith, I. J., Godinez, G. L., Singh, B. K., McCaughey, K. M., Alcantara, R. R., Gururaja, T., Ho, M. S., Nguyen, H. N., Friera, A. M., White, K. A., McLaughlin, J. R., Hansen, D., Romero, J. M., Baltgalvis, K. A., Claypool, M. D., Li, W., Lang, W., Yam, G. C., Gelman, M. S., Ding, R., Yung, S. L., Creger, D. P., Chen, Y., Singh, R., Smuder, A. J., Wiggs, M. P., Kwon, O.-S., Sollanek, K. J., Powers, S. K., Masuda, E. S., Taylor, V. C., Payan, D. G., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.
控制性机械通气（CMV）与膈肌萎缩和收缩功能障碍的发展有关，呼吸肌无力被认为是导致患者脱机延迟的重要原因。因此，预防这些过程的治疗策略可能具有临床益处。本研究旨在探讨 Janus 激酶（JAK）/信号转导和转录激活因子 3（STAT3）信号通路在 CMV 介导的大鼠膈肌耗竭和无力中的作用。CMV 诱导的膈肌萎缩和收缩功能障碍与 STAT3 酪氨酸 705（Tyr705）和丝氨酸 727（Ser727）磷酸化的显著增加同时发生。STAT3 激活伴随着其向膈肌肌内线粒体的易位和线粒体功能障碍。CMV 期间 JAK 信号的抑制阻止了 STAT3 上两个靶位的磷酸化，消除了磷酸化 STAT3 在线粒体中的积累，并逆转了线粒体功能的病理改变，减少了膈肌的氧化应激，维持了正常的膈肌收缩性。此外，CMV 期间 JAK 抑制减弱了膈肌中关键蛋白水解途径的激活以及膈肌萎缩。这些发现表明 JAK/STAT3 信号通路参与了 CMV 期间膈肌肌肉萎缩和功能障碍的发生，并表明与 CMV 相关的延迟拔管时间可以通过抑制 Janus 激酶信号来预防。-Smith, I. J., Godinez, G. L., Singh, B. K., McCaughey, K. M., Alcantara, R. R., Gururaja, T., Ho, M. S., Nguyen, H. N., Friera, A. M., White, K. A., McLaughlin, J. R., Hansen, D., Romero, J. M., Baltgalvis, K. A., Claypool, M. D., Li, W., Lang, W., Yam, G. C., Gelman, M. S., Ding, R., Yung, S. L., Creger, D. P., Chen, Y., Singh, R., Smuder, A. J., Wiggs, M. P., Kwon, O.-S., Sollanek, K. J., Powers, S. K., Masuda, E. S., Taylor, V. C., Payan, D. G., Kinoshita, T., Kinsella, T. M. 在控制性机械通气期间抑制 Janus 激酶信号可预防通气引起的膈肌功能障碍。
