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Molecular Medicine

, Volume 20, Issue 1, pp 579–589 | Cite as

The JAK-STAT Pathway Is Critical in Ventilator-Induced Diaphragm Dysfunction

  • Huibin Tang
  • Ira J. Smith
  • Sabah N. A. Hussain
  • Peter Goldberg
  • Myung Lee
  • Sista Sugiarto
  • Guillermo L. Godinez
  • Baljit K. Singh
  • Donald G. Payan
  • Thomas A. Rando
  • Todd M. Kinsella
  • Joseph B. Shrager
Research Article

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.

Notes

Acknowledgments

We are grateful to Lawrence Argetsinger (University of Michigan) for providing JAK2 plasmids for this study. We also thank Bianca Kapoor and Isaac Ghansah, and Kun Wang and Yang Gao (Stanford University); and Kelly M McCaughey and Raniel R Alcantara (Rigel Pharmaceuticals) for technical assistance. This work is supported by a Veterans Administration (VA) Biomedical Laboratory R&D Merit Review grant to JB Shrager, and by the grants from the NIH (TR01 AG047820 and R37 AG023806) and the VA (Biomedical Laboratory R&D and Rehab R&D) Merit Reviews to TA Rando.

Supplementary material

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Authors and Affiliations

  • Huibin Tang
    • 1
    • 2
  • Ira J. Smith
    • 3
  • Sabah N. A. Hussain
    • 4
  • Peter Goldberg
    • 4
  • Myung Lee
    • 1
    • 2
  • Sista Sugiarto
    • 1
    • 2
  • Guillermo L. Godinez
    • 3
  • Baljit K. Singh
    • 3
  • Donald G. Payan
    • 3
  • Thomas A. Rando
    • 5
    • 6
  • Todd M. Kinsella
    • 3
  • Joseph B. Shrager
    • 1
    • 2
  1. 1.Division of Thoracic Surgery, Department of Cardiothoracic SurgeryStanford University School of Medicine, 2nd floor, Falk buildingStanfordUSA
  2. 2.Veterans Administration Palo Alto Healthcare SystemPalo AltoUSA
  3. 3.Rigel Pharmaceuticals, Inc.South San FranciscoUSA
  4. 4.Critical Care DivisionRoyal Victoria HospitalMontrealCanada
  5. 5.Department of Neurology and Neurological ScienceStanford University School of MedicineStanfordUSA
  6. 6.Neurology ServiceVeterans Administration Palo Alto Healthcare SystemPalo AltoUSA

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