title: The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.
abstract: 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 ~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.
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, United States of America.|Veterans Administration Palo Alto Healthcare System, Palo Alto, California, United States of America.
authors.forename: Huibin
authors.initials: H
authors.lastname: Tang
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Smith
authors.affiliation: Critical Care Division, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: Sabah N A
authors.initials: SN
authors.lastname: Hussain
authors.affiliation: Critical Care Division, Royal Victoria Hospital, Montreal, Quebec, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Goldberg
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, United States of America.|Veterans Administration Palo Alto Healthcare System, Palo Alto, California, United States of America.
authors.forename: Myung
authors.initials: M
authors.lastname: Lee
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, United States of America.|Veterans Administration Palo Alto Healthcare System, Palo Alto, California, United States of America.
authors.forename: Sista
authors.initials: S
authors.lastname: Sugiarto
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Guillermo L
authors.initials: GL
authors.lastname: Godinez
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Baljit K
authors.initials: BK
authors.lastname: Singh
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Payan
authors.affiliation: Department of Neurology and Neurological Science, Stanford University School of Medicine, Stanford, California, United States of America.|Neurology Service, Veterans Administration Palo Alto Healthcare System, Palo Alto, California, United States of America.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Rando
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kinsella
authors.affiliation: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, United States of America.|Veterans Administration Palo Alto Healthcare System, Palo Alto, California, United States of America.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Shrager
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D003964:Diaphragm / Q000378:metabolism* / Q000503:physiopathology; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050791:STAT Transcription Factors; D000255:Adenosine Triphosphate; D053612:Janus Kinases