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

• Published in: American journal of respiratory and critical care medicine 2001-03, Vol.163 (3), p.753-761
• Main Authors: TAILLE, Camille, FORESTI, Roberta, LANONE, Sophie, ZEDDA, Christine, GREEN, Colin, AUBIER, Michel, MOTTERLINI, Roberto, BOCZKOWSKI, Jorge
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Diaphragm - chemistry; Diaphragm - physiopathology; Emergency and intensive care: infection, septic shock; Endotoxemia - complications; Endotoxins - pharmacology; Escherichia coli; Escherichia coli Infections - complications; heme oxygenase; Heme Oxygenase (Decyclizing) - antagonists & inhibitors; Heme Oxygenase (Decyclizing) - physiology; Intensive care medicine; Male; Malondialdehyde - analysis; Medical sciences; Protoporphyrins - pharmacology; Rats; Rats, Sprague-Dawley
• ISSN: 1073-449X; 1535-4970
• 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.