Alpha 2A-adrenoreceptor blockade improves sepsis-induced acute lung injury accompanied with depressed high mobility group box-1 levels in rats

Purpose: To investigate the effects of alpha 2A-adrenoreceptor blockade on acute lung injury (ALI) and high mobility group box-1 protein (HMGB1) expression in a rat model of sepsis. Methods: Sepsis was induced in male rats by cecal ligation and puncture (CLP). Thirty adult male Sprague-Dawley rats were equally randomized to the Sham group, the CLP group, and the CLP + maleate group. Five hours after CLP, rats received an intraperitoneal injection of BRL-44408 maleate or the same volume of vehicle. Serum levels of TNF-alpha, IL-6, IL-10, HMGB1, and norepinephrine were measured at baseline, 6, 18, and 24 h after CLP. Lung TNF-alpha, IL-6, IL-10, immunohistochemical and western blotting analysis of HMGB1, nuclear factor (NF)-kappa B activation, myeloperoxidase (MPO) activity, histological scores, and wet-to-dry weight ratio were determined 24 h after CLP. In additional CLP and CLP + maleate groups, the 7 day survival rate was evaluated. Results: Compared with the CLP group, serum TNF-alpha at 6 h, HMGB1 at 18 and 24 h, and norepinephrine at 6 and 18 h after CLP decreased in the CLP + maleate group. Lung TNF-alpha, IL-6, and HMGB1 expressions decreased at 24 h after CLP. NF-kappa B activation, MPO activity, histological scores, and wet-to-dry weight ratio were lower in the CLP + maleate group than the CLP group. There was no significant difference in 7 day survival rate between the CLP and CLP + maleate groups. Conclusions: The alpha 2A-adrenoreceptor blockade by a specific antagonist maleate improves sepsis-induced acute lung injury accompanied with depressed HMGB1 expression in rats. The mechanism seemed to be mediated partly through downregulation of the signal transductions of the NF-kappa B pathway. (c) 2012 Elsevier Ltd. All rights reserved.