title: Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.
abstract: 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.
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Smith
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Guillermo L
authors.initials: GL
authors.lastname: Godinez
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Baljit K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McCaughey
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Raniel R
authors.initials: RR
authors.lastname: Alcantara
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Tarikere
authors.initials: T
authors.lastname: Gururaja
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Ho
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Annabelle M
authors.initials: AM
authors.lastname: Friera
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Kathy A
authors.initials: KA
authors.lastname: White
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: John R
authors.initials: JR
authors.lastname: McLaughlin
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Derek
authors.initials: D
authors.lastname: Hansen
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Romero
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Baltgalvis
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Claypool
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Wayne
authors.initials: W
authors.lastname: Lang
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: George C
authors.initials: GC
authors.lastname: Yam
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Gelman
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Rongxian
authors.initials: R
authors.lastname: Ding
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Yung
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Creger
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Wiggs
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
authors.forename: Oh-Sung
authors.initials: OS
authors.lastname: Kwon
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Sollanek
authors.affiliation: Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, Florida, USA.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Esteban S
authors.initials: ES
authors.lastname: Masuda
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Taylor
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and.
authors.forename: Taisei
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, USA; and tkinsella@rigel.com.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kinsella
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018908:Muscle Weakness / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D014443:Tyrosine; D012694:Serine; D053612:Janus Kinases
keywords: STAT3; mitochondria; muscle wasting; oxidative stress