title: Nuclear factor-κB signaling contributes to mechanical ventilation-induced diaphragm weakness*.
abstract: OBJECTIVE
  Although mechanical ventilation is a life-saving measure for patients in respiratory failure, prolonged mechanical ventilation results in diaphragmatic weakness attributable to fiber atrophy and contractile dysfunction. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragmatic weakness is important. In this context, it is established that oxidative stress is required for mechanical ventilation-induced diaphragmatic weakness to occur. Numerous redox-sensitive signaling pathways exist in muscle including the transcription factor nuclear factor-κB. Although it has been suggested that nuclear factor-κB contributes to proteolytic signaling in inactivity-induced atrophy in locomotor muscles, the role that nuclear factor-κB plays in mechanical ventilation-induced diaphragmatic weakness is unknown. We tested the hypothesis that nuclear factor-κB activation plays a key signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is required for nuclear factor-κB activation.
  
  
  METHODS
  Cause and effect was determined by independently treating mechanically ventilated animals with either a specific nuclear factor-κB inhibitor (SN50) or a clinically relevant antioxidant (curcumin).
  
  
  RESULTS
  Inhibition of nuclear factor-κB activity partially attenuated both mechanical ventilation-induced diaphragmatic atrophy and contractile dysfunction. Further, treatment with the antioxidant curcumin prevented mechanical ventilation-induced activation of nuclear factor-κB in the diaphragm and rescued the diaphragm from both mechanical ventilation-induced atrophy and contractile dysfunction.
  
  
  CONCLUSIONS
  Collectively, these findings support the hypothesis that nuclear factor-κB activation plays a significant signaling role in mechanical ventilation-induced diaphragmatic weakness and that oxidative stress is an upstream activator of nuclear factor-κB. Finally, our results suggest that prevention of mechanical ventilation-induced oxidative stress in the diaphragm could be a useful clinical strategy to prevent or delay mechanical ventilation-induced diaphragmatic weakness.
authors.affiliation: Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, FL, USA.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Hudson
authors.forename: W Bradley
authors.initials: WB
authors.lastname: Nelson
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kavazis
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000378:metabolism; D005260:Female; D018908:Muscle Weakness / Q000209:etiology* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D012122:Ventilators, Mechanical / Q000009:adverse effects*
chemical_list: D016328:NF-kappa B
references.citation: J Physiol. 2005 May 15;565(Pt 1):309-23
references.pmid: 15774533
references.citation: J Clin Invest. 2004 Nov;114(10):1504-11
references.pmid: 15546001
references.citation: N Engl J Med. 2008 Mar 27;358(13):1327-35
references.pmid: 18367735
references.citation: J Appl Physiol (1985). 2006 Oct;101(4):1017-24
references.pmid: 16675618
references.citation: Cell Mol Life Sci. 2008 Jun;65(11):1631-52
references.pmid: 18324353
references.citation: Adv Exp Med Biol. 2007;595:471-80
references.pmid: 17569225
references.citation: J Appl Physiol (1985). 2007 Mar;102(3):1143-51
references.pmid: 17122379
references.citation: J Physiol. 2007 Nov 15;585(Pt 1):203-15
references.pmid: 17916612
references.citation: Mediators Inflamm. 2008;2008:317851
references.pmid: 18389075
references.citation: Am J Respir Crit Care Med. 2007 Jan 15;175(2):150-9
references.pmid: 17082496
references.citation: Gynecol Obstet Invest. 2008;65(3):174-86
references.pmid: 18025832
references.citation: Muscle Nerve. 2006 Feb;33(2):155-65
references.pmid: 16228971
references.citation: Oncogene. 1998 Dec 24;17(25):3225-36
references.pmid: 9916985
references.citation: Am J Respir Crit Care Med. 2003 Jan 15;167(2):120-7
references.pmid: 12411288
references.citation: J Appl Physiol (1985). 2003 Sep;95(3):1116-24
references.pmid: 12777408
references.citation: PLoS One. 2011 Jan 13;6(1):e16171
references.pmid: 21249144
references.citation: Biochemistry. 1996 Apr 2;35(13):3899-908
references.pmid: 8672420
references.citation: Am J Respir Crit Care Med. 2004 Dec 1;170(11):1179-84
references.pmid: 15374845
references.citation: Free Radic Biol Med. 2008 Jan 15;44(2):169-79
references.pmid: 18191753
references.citation: Am J Respir Crit Care Med. 2005 Nov 15;172(10):1267-75
references.pmid: 16126937
references.citation: Exp Gerontol. 2005 Jun;40(6):526-31
references.pmid: 15963672
references.citation: J Cell Biochem. 2002;85(2):334-45
references.pmid: 11948689
references.citation: Am J Physiol. 1986 Mar;250(3 Pt 1):C474-9
references.pmid: 3953809
references.citation: Am J Physiol Cell Physiol. 2004 Oct;287(4):C834-43
references.pmid: 15355854
references.citation: Monaldi Arch Chest Dis. 1994 Dec;49(6):522-6
references.pmid: 7711707
references.citation: J Appl Physiol (1985). 2009 Feb;106(2):385-94
references.pmid: 18974366
references.citation: N Engl J Med. 1995 Feb 9;332(6):345-50
references.pmid: 7823995
references.citation: J Immunol. 1999 Sep 15;163(6):3474-83
references.pmid: 10477620
references.citation: Am J Physiol. 1989 Aug;257(2 Pt 2):R300-5
references.pmid: 2764153
references.citation: Am J Respir Crit Care Med. 2002 Nov 15;166(10):1369-74
references.pmid: 12421745
references.citation: J Appl Physiol (1985). 2010 May;108(5):1376-82
references.pmid: 20203072
references.citation: Am J Respir Crit Care Med. 2004 Nov 1;170(9):994-9
references.pmid: 15297271
references.citation: J Surg Res. 2009 Mar;152(1):46-53
references.pmid: 19027920
references.citation: Immun Ageing. 2005 Nov 04;2:15
references.pmid: 16271147
references.citation: Oncogene. 1999 Nov 22;18(49):6910-24
references.pmid: 10602466
references.citation: Crit Care Med. 2011 Jul;39(7):1749-59
references.pmid: 21460706
references.citation: Chest. 2011 Apr;139(4):816-824
references.pmid: 21106654
references.citation: Am J Respir Crit Care Med. 2007 Jun 1;175(11):1134-8
references.pmid: 17379854