Protective role of heme oxygenases against endotoxin-induced diaphragmatic dysfunction in rats.

Abstract

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.

• Authors: C Taillé, R Foresti, S Lanone, C Zedda, C Green, M Aubier, R Motterlini, J Boczkowski
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 163 Issue 3 Pt 1 Pg. 753-61 (Mar 2001) ISSN: 1073-449X [Print] United States
• PMID: 11254535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endotoxins
• Protoporphyrins
• zinc protoporphyrin
• Malondialdehyde
• Heme Oxygenase (Decyclizing)

Topics

• Animals
• Diaphragm (chemistry, physiopathology)
• Endotoxemia (complications)
• Endotoxins (pharmacology)
• Escherichia coli Infections (complications)
• Heme Oxygenase (Decyclizing) (antagonists & inhibitors, physiology)
• Male
• Malondialdehyde (analysis)
• Protoporphyrins (pharmacology)
• Rats
• Rats, Sprague-Dawley