Protective role of heme oxygenases against endotoxin-induced diaphragmatic dysfunction in rats.
Reactive oxygen species are strongly implicated in diaphragmatic dysfunction during sepsis. We investigated whether the heme oxygenase (HO) pathway, which is a powerful protective cellular system, protects the diaphragm against oxidative stress and contractile failure during sepsis. A basal expression of both the inducible and constitutive HO protein isoforms (HO-1 and HO-2, respectively) was found in the diaphragm. Enhanced HO-1 expression in diaphragmatic myocytes was observed 24 h after Escherichia coli endotoxin (lipopolysaccharide, LPS) inoculation and remained elevated for at least 96 h. Enhanced HO-1 expression was also observed in the rectus abdominis and soleus muscles and in the left ventricular myocardium of endotoxemic animals. Diaphragmatic HO-2 expression was not modified by endotoxin. Diaphragmatic HO activity exhibited a biphasic time course characterized by a transient decrease during the first 12 h followed by a significant increase at 24 h, corresponding to HO-1 induction. Diaphragmatic force was significantly reduced 24 h after LPS, concomitantly with muscular oxidative stress. Administation of an inhibitor of heme oxygenase activity, zinc protoporphyrin IX (ZnPP-IX), further impaired muscular oxidative stress and contractile failure. By contrast, increased levels of HO-1 expression obtained by pretreatment of rats with hemin, a powerful inducer of HO-1, completely prevented LPS-mediated diaphragmatic oxidative stress and contractile failure. This protective effect was reversed by ZnPP-IX. These results show an important protective role for the HO pathway against sepsis-induced diaphragmatic dysfunction, which could be related to its antioxidant properties.
Institut National de la Santé et de la Recherche Médicale U408, Faculté Xavier Bichat, Paris, France.
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C
Taillé
R
R
Foresti
S
S
Lanone
C
C
Zedda
C
C
Green
M
M
Aubier
R
R
Motterlini
J
J
Boczkowski
D000818:Animals; D003964:Diaphragm / Q000737:chemistry / Q000503:physiopathology*; D019446:Endotoxemia / Q000150:complications*; D004731:Endotoxins / Q000494:pharmacology*; D004927:Escherichia coli Infections / Q000150:complications*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004731:Endotoxins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D008315:Malondialdehyde; D006419:Heme Oxygenase (Decyclizing)