Dataset Information

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.

SUBMITTER: Tang H

PROVIDER: S-EPMC4365068 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.

Tang Huibin H Smith Ira J IJ Hussain Sabah N A SN Goldberg Peter P Lee Myung M Sugiarto Sista S Godinez Guillermo L GL Singh Baljit K BK Payan Donald G DG Rando Thomas A TA Kinsella Todd M TM Shrager Joseph B JB

Molecular medicine (Cambridge, Mass.) 20150219

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 ...[more]

PMID: 25286450

Similar Datasets

Project description:BackgroundThe effects of different modes of mechanical ventilation in the same ventilatory support level on ventilator-induced diaphragm dysfunction onset were assessed in healthy rabbits.MethodsTwenty New Zealand rabbits were randomly assigned to 4 groups (n = 5 in each group). Group 1: no mechanical ventilation; group 2: controlled mechanical ventilation (CMV) for 24 hours; group 3: assist/control ventilation (A/C) mode for 24 hours; group 4: high-level pressure support ventilation (PSV) mode for 24 hours. Heart rate, mean arterial blood pressure, PH, partial pressure of arterial oxygen/fraction of inspired oxygen and partial pressure of arterial carbon dioxide were monitored and diaphragm electrical activity was analyzed in the 4 groups. Caspase-3 was evaluated by protein analysis and diaphragm ultra structure was assessed by electron microscopy.ResultsThe centroid frequency and the ratio of high frequency to low frequency were significantly reduced in the CMV, A/C and PSV groups (P < 0.001). The percent change in centroid frequency was significantly lower in the PSV group than in the CMV and A/C groups (P = 0.001 and P = 0.028, respectively). Electromyography of diaphragm integral amplitude decreased by 90% ± 1.48%, 67.8% ± 3.13% and 70.2% ± 4.72% in the CMV, A/C and PSV groups, respectively (P < 0.001). Caspase-3 protein activation was attenuated in the PSV group compared with the CMV and A/C groups (P = 0.035 and P = 0.033, respectively). Irregular swelling of mitochondria along with fractured and fuzzy cristae was observed in the CMV group, whereas mitochondrial cristae were dense and rich in the PSV group. The mitochondrial injury scores (Flameng scores) in the PSV group were the lowest among the 3 ventilatory groups (0.93 ± 0.09 in PSV versus 2.69 ± 0.05 in the CMV [P < 0.01] and PSV versus A/C groups [2.02 ± 0.08, P < 0.01]).ConclusionsThe diaphragm myoelectric activity was reduced in the PSV group, although excessive oxidative stress and ultra-structural changes of diaphragm were found. However, partial diaphragm electrical activity was retained and diaphragm injury was minimized using the PSV mode.

Project description:BackgroundThe JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains.Methods & findingsWe used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin.ConclusionsAminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low-dose methotrexate. In addition, we suggest that patients with JAK/STAT-associated haematological malignancies may benefit from low-dose methotrexate treatments. While the JAK1/2 inhibitor ruxolitinib is effective, a £43,200 annual cost precludes widespread adoption. With an annual methotrexate cost of around £32, our findings represent an important development with significant future potential.

Dataset Information

The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.

Publications

The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets