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

Am J Respir Crit Care Med. 2001 Mar;163(3 Pt 1):753-61. doi: 10.1164/ajrccm.163.3.2004202.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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