Role of heme oxygenases in sepsis-induced diaphragmatic contractile dysfunction and oxidative stress.
Heme oxygenases (HOs), essential enzymes for heme metabolism, play an important role in the defense against oxidative stress. In this study, we evaluated the expression and functional significance of HO-1 and HO-2 in the ventilatory muscles of normal rats and rats injected with bacterial lipopolysaccharide (LPS). Both HO-1 and HO-2 proteins were detected inside ventilatory and limb muscle fibers of normal rats. Diaphragmatic HO-1 and HO-2 expressions rose significantly within 1 and 12 h of LPS injection, respectively. Inhibition of the activity of inducible nitric oxide synthase (iNOS) in rats and absence of this isoform in iNOS(-/-) mice did alter sepsis-induced regulation of muscle HOs. Systemic inhibition of HO activity with chromium mesoporphyrin IX enhanced muscle protein oxidation and hydroxynonenal formation in both normal and septic rats. Moreover, in vitro diaphragmatic force generation declined substantially in response to HO inhibition both in normal and septic rats. We conclude that both HO-1 and HO-2 proteins play an important role in the regulation of muscle contractility and in the defense against sepsis-induced oxidative stress.
Department of Respiratory Medicine, Hospital del Mar-Municipal Institute of Medical Research, Pompeu Fabra University, 08003 Barcelona, Spain.
Esther
E
Barreiro
Alain S
AS
Comtois
Shawn
S
Mohammed
Larry C
LC
Lands
Sabah N A
SN
Hussain
D000818:Animals; D003964:Diaphragm / Q000503:physiopathology*; D004927:Escherichia coli Infections / Q000503:physiopathology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism / Q000502:physiology*; D051547:Heme Oxygenase-1; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D008565:Membrane Proteins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C105245:heme oxygenase-2