G S Supinski

University of Kentucky, Lexington, Kentucky, United States

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Publications (117)541.96 Total impact

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    ABSTRACT: Rationale: Recent work indicates that infections are a major contributor to diaphragm weakness in critically ill mechanically ventilated patients, and that diaphragm weakness is a risk factor for death and prolonged mechanical ventilation. Infections activate muscle calpain, but many believe this is an epiphenomenon and that other proteolytic processes are responsible for infection-induced muscle weakness. Objectives: We tested the hypothesis that muscle-specific overexpression of calpastatin (endogenous calpain inhibitor, CalpOX) would attenuate diaphragm dysfunction in cecal ligation puncture (CLP)-induced sepsis. Methods: We studied: (a) wild type (WT) sham-operated mice, (b) WT CLP-operated mice, (c) CalpOX sham-operated mice and (d) CalpOX CLP-operated mice (n=9-10/group). Twenty-four hours after surgery, we assessed the diaphragm force-frequency relationship, diaphragm mass and total protein content and diaphragm levels of talin and myosin heavy chain (MHC). Results: CLP markedly reduced diaphragm specific force generation (force/CSA) which was prevented by calpastatin overexpression (force averaged 21.4 ± 0.5, 6.9 ± 0.8, 22.4 ± 1.0, and 18.3 ± 1.3 N/cm2, respectively, for WT sham, WT CLP, CalpOX sham, and CalpOx CLP groups, p<0.001). Diaphragm mass and total protein content were similar in all groups. CLP induced talin cleavage and reduced MHC levels; CalpOX prevented these alterations. Conclusions: CLP-induced sepsis rapidly reduces diaphragm specific force generation and is associated with cleavage and/or depletion of key muscle proteins (talin, MHC), effects prevented by muscle-specific calpastatin overexpression. These data indicate that calpain activation is a major cause of diaphragm weakness in response to CLP-induced sepsis.
    Journal of Applied Physiology 08/2014; · 3.43 Impact Factor
  • Gerald S. Supinski, Leigh Ann Callahan
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    ABSTRACT: Infections induce severe respiratory muscle weakness. Currently there are no treatments for this important clinical problem. We tested the hypothesis that β-hydroxy-β-methylbutyrate (HMB) would prevent sepsis-induced diaphragm weakness. Four groups of adult male mice were studied: controls (saline-injected), sepsis (intraperitoneal lipopolysaccharide), sepsis + HMB (injected intravenously), and HMB. Diaphragm force generation and indices of caspase 3, calpain, 20S proteasomal subunit, and double-stranded RNA-dependent protein kinase (PKR) activation were assessed after 24 hours. Sepsis elicited large reductions in diaphragm specific force generation at all stimulation frequencies. Endotoxin also activated caspase 3, calpain, the 20S proteasomal subunit and PKR in the diaphragm. HMB blocked sepsis-induced caspase 3, 20S proteasomal and PKR activation, but did not prevent calpain activation. Most importantly, HMB administration significantly attenuated sepsis-induced diaphragm weakness, preserving muscle force generation at all stimulation frequencies (p < 0.01). We speculate that HMB may prove to be an important therapy in infected patients, with the potential to increase diaphragm strength, to reduce the duration of mechanical ventilation and to decrease mortality in this patient population.
    Respiratory Physiology & Neurobiology 06/2014; · 1.97 Impact Factor
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    Leigh A Callahan, Gerald S Supinski
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    ABSTRACT: A major consequence of ICU-acquired weakness (ICUAW) is diaphragm weakness, which prolongs the duration of mechanical ventilation. Hyperglycemia (HG) is a risk factor for ICUAW. However, the mechanisms underlying HG-induced respiratory muscle weakness are not known. Excessive reactive oxygen species (ROS) are known to injure multiple tissues during HG, but only one study has suggested that excessive ROS generation may be linked to HG-induced diaphragm weakness. We tested the hypothesis that HG-induced diaphragm dysfunction is mediated by excessive superoxide generation and that administration of a specific superoxide scavenger, polyethylene glycol superoxide dismutase (PEG-SOD), would ameliorate these effects.
    Critical care (London, England) 05/2014; 18(3):R88. · 5.04 Impact Factor
  • Leigh Ann Callahan, Gerald S Supinski
    Critical care medicine 10/2013; 41(10):2457-8. · 6.15 Impact Factor
  • Leigh Ann Callahan, Gerald S Supinski
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    ABSTRACT: No abstract; this is an invited editorial from Dr. deTroyer.
    Journal of Applied Physiology 07/2013; · 3.43 Impact Factor
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    Gerald S Supinski, Leigh Ann Callahan
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    ABSTRACT: Studies indicate that mechanically ventilated patients develop significant diaphragm muscle weakness, but the etiology of weakness and its clinical impact remain incompletely understood. We assessed diaphragm strength in mechanically ventilated medical intensive care unit (MICU) patients, correlated the development of diaphragm weakness with multiple clinical parameters, and examined the relationship between the level of diaphragm weakness and patient outcomes. Transdiaphragmatic twitch pressure (PdiTw) in response to bilateral magnetic stimulation of the phrenic nerves was measured. Diaphragm weakness was correlated with the presence of infection, blood urea nitrogen, albumin, and glucose levels. The relationship of diaphragm strength to patient outcomes, including mortality and the duration of mechanical ventilation for successfully weaned patients, was also assessed. We found that infection is a major risk factor for diaphragm weakness in mechanically ventilated MICU patients. Outcomes for patients with severe diaphragm weakness (PdiTw < 10 cm H2O) were poor, with a markedly increased mortality (49%) compared to patients with PdiTw [greater than or equal to] 10 cm H2O (7% mortality, P=0.022). In addition, survivors with PdiTw < 10 cm H2O required a significantly longer duration of mechanical ventilation (12.3 +/- 1.7 days) than those with PdiTw [greater than or equal to] 10 cm H2O (5.5 +/- 2.0 days, P=0.016). Infection is a major cause of severe diaphragm weakness in mechanically ventilated patients. Moreover, diaphragm weakness is an important determinant of poor outcomes in this patient population.
    Critical care (London, England) 06/2013; 17(3):R120. · 5.04 Impact Factor
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • Gerald S. Supinski, Leigh Ann P. Callahan
    American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
  • Gerald S. Supinski, Leigh Ann Callahan
    American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Leigh Ann Callahan, Gerald S. Supinski
    American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Gerald S. Supinski
    American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Gerald S. Supinski, Leigh Ann Callahan
    American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Leigh Ann P. Callahan, Gerald S. Supinski
    American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • G S Supinski, L A Callahan
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    ABSTRACT: Diaphragm caspase-8 activation plays a key role in modulating sepsis-induced respiratory muscle dysfunction. It is also known that double-stranded RNA-dependent protein kinase (PKR) is a regulator of caspase-8 activation in neural tissue. We tested the hypothesis that the PKR pathway modulates sepsis-induced diaphragmatic caspase-8 activation. We first evaluated the time course of diaphragm PKR activation following endotoxin administration in mice. We then determined whether administration of a PKR inhibitor (2-aminopurine) prevents endotoxin-induced diaphragm caspase-8 activation and contractile dysfunction in mice. Finally, we investigated if inhibition of PKR (using either 2-aminopurine or transfection with dominant-negative PKR) blocks caspase-8 activation in cytokine treated C₂C₁₂ cells. Endotoxin markedly activated diaphragm PKR (with increases in both active phospho-PKR protein levels, P < 0.03, and directly measured PKR activity, P < 0.01) and increased active caspase-8 levels (P < 0.01). Inhibition of PKR with 2-aminopurine prevented endotoxin-induced diaphragm caspase-8 activation (P < 0.01) and diaphragm weakness (P < 0.001). Inhibition of PKR with either 2-aminopurine or transfection with dominant-negative PKR blocked caspase-8 activation in isolated cytokine-treated C₂C₁₂ cells. These data implicate PKR activation as a major factor mediating cytokine-induced skeletal muscle caspase-8 activation and weakness.
    Journal of Applied Physiology 11/2010; 110(1):199-205. · 3.43 Impact Factor
  • Leigh Ann P. Callahan, Xiao Song, Lin Wang, Gerald S. Supinski
    American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
  • Source
    Gerald S Supinski, Jonas Vanags, Leigh Ann Callahan
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    ABSTRACT: Infections produce severe respiratory muscle weakness, which contributes to the development of respiratory failure. An effective, safe therapy to prevent respiratory muscle dysfunction in infected patients has not been defined. This study examined the effect of eicosapentaenoic acid (EPA), an immunomodulator that can be safely administered to patients, on diaphragm force generation following endotoxin administration. Rats were administered the following (n = 5/group): (a) saline, (b) endotoxin, 12 mg/kg IP, (c) endotoxin + EPA (1.0 g/kg/d), and (d) EPA alone. Diaphragms were removed and measurements made of the diaphragm force-frequency curve, calpain activation, caspase activation, and protein carbonyl levels. Endotoxin elicited large reductions in diaphragm specific force generation (P < 0.001), and increased diaphragm caspase activation (P < 0.01), calpain activation (P < 0.001) and protein carbonyl levels (P < 0.01). EPA administration attenuated endotoxin-induced reductions in diaphragm specific force, with maximum specific force levels of 27 +/- 1, 14 +/- 1, 23 +/- 1, and 24 +/- 1 N/cm2, respectively, for control, endotoxin, endotoxin + EPA, and EPA treated groups (P < 0.001). EPA did not prevent endotoxin induced caspase activation or protein carbonyl formation but significantly reduced calpain activation (P < 0.02). These data indicate that endotoxin-induced reductions in diaphragm specific force generation can be partially prevented by administration of EPA, a nontoxic biopharmaceutical that can be safely given to patients. We speculate that it may be possible to reduce infection-induced skeletal muscle weakness in critically ill patients by administration of EPA.
    Critical care (London, England) 03/2010; 14(2):R35. · 5.04 Impact Factor

Publication Stats

2k Citations
541.96 Total Impact Points

Institutions

  • 2007–2014
    • University of Kentucky
      • Department of Medicine
      Lexington, Kentucky, United States
  • 2005–2007
    • Georgia Health Sciences University
      • Medical College of Georgia
      Augusta, GA, United States
    • Medical College of Georgia
      Augusta, Georgia, United States
  • 1988–2002
    • Case Western Reserve University
      • • Department of Physiology and Biophysics
      • • Department of Medicine (University Hospitals Case Medical Center)
      • • MetroHealth Medical Center
      Cleveland, OH, United States
  • 2001
    • Case Western Reserve University School of Medicine
      • Department of Medicine
      Cleveland, Ohio, United States
  • 1990–1999
    • MetroHealth Medical Center
      Cleveland, Ohio, United States
    • Metro Health Hospital
      Wyoming, Michigan, United States