Activation of autophagy is involved in the protective effect of 17β‐oestradiol on endotoxaemia‐induced multiple organ dysfunction in ovariectomized rats

Oestrogens have been reported to attenuate acute inflammation in sepsis. In this study, the effects of long‐term oestrogen replacement with 17β‐oestradiol (E₂) on endotoxaemia‐induced circulatory dysfunction and multiple organ dysfunction syndrome were evaluated in ovariectomized (Ovx) rats. E₂ (50 μg/kg, s.c., 3 times/week) was administered for 8 weeks, followed by the induction of endotoxaemia by intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg/4 hrs). Oestrogen deficiency induced by ovariectomy for 9 weeks augmented the LPS‐induced damage, including endotoxic shock, myocardial contractile dysfunction, renal dysfunction and rhabdomyolysis. Cardiac levels of NF‐κB p65, iNOS and oxidized glutathione, free radical production in skeletal muscles, myoglobin deposition in renal tubules, and plasma levels of plasminogen activator inhibitor‐1, TNF‐α, and IL‐6 were more pronounced in the Ovx + LPS group than in the Sham + LPS group. Long‐term treatment of E₂ prevented this amplified damage in Ovx rats. Six hours after LPS initiation, activation of the autophagic process, demonstrated by increases in Atg12 and LC3B‐II/LC3B‐I ratios, and induction of haem oxygenase (HO)‐1 and heat‐shock protein (HSP) 70 protein expression in myocardium were increased significantly in the Ovx + E₂ + LPS group. These results suggest that activation of autophagy and induction of HO‐1 and HSP70 contribute to the protective effect of long‐term E₂ replacement on multiple organ dysfunction syndrome in endotoxaemia.