Premium
Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation‐induced diaphragm dysfunction
Author(s) -
Smith Ira J.,
Godinez Guillermo L.,
Singh Baljit K.,
McCaughey Kelly M.,
Alcantara Raniel R.,
Gururaja Tarikere,
Ho Melissa S.,
Nguyen Henry N.,
Friera Annabelle M.,
White Kathy A.,
McLaughlin John R.,
Hansen Derek,
Romero Jason M.,
Baltgalvis Kristen A.,
Claypool Mark D.,
Li Wei,
Lang Wayne,
Yam George C.,
Gelman Marina S.,
Ding Rongxian,
Yung Stephanie L.,
Creger Daniel P.,
Chen Yan,
Singh Rajinder,
Smuder Ashley J.,
Wiggs Michael P.,
Kwon OhSung,
Sollanek Kurt J.,
Powers Scott K.,
Masuda Esteban S.,
Taylor Vanessa C.,
Payan Donald G.,
Kinoshita Taisei,
Kinsella Todd M.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-244210
Subject(s) - janus kinase , diaphragm (acoustics) , mechanical ventilation , ventilation (architecture) , microbiology and biotechnology , medicine , signal transduction , chemistry , biology , engineering , electrical engineering , mechanical engineering , loudspeaker
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. FASEB J . 28, 2790–2803 (2014). www.fasebj.org