4F, apolipoprotein AI mimetic peptide, attenuates acute lung injury and improves survival in endotoxemic rats

Abstract

BACKGROUND: 4F, apolipoprotein AI mimetic peptide, mimics anti-inflammatory properties of high-density lipoprotein (HDL). The aim of this study was to investigate whether 4F attenuates acute lung injury and improves survival in endotoxemic rats and to determine whether the therapeutic benefits of 4F are associated with the stimulation of sphingosine-1-phosphate receptor 1 (S1P(1)), the activation of Akt, the down-regulation of the nuclear factor-kappa B (NF-kappa B) pathway, and the suppression of cell adhesion molecules. METHODS: To induce endotoxemia in rats, lipopolysaccharide (LPS, 10 mg/kg) was injected into a tail vein and 10 minutes later, vehicle or 4F (10 mg/kg) was administered intraperitoneally, respectively. We observed the survival of subjects for 72 hours. At 6-hour post-LPS, we killed animals and measured S1P(1) expression, phosphorylated Akt/Akt ratio, cytoplasmic phosphorylated inhibitor kappa B-alpha/inhibitor kappa B-alpha ratio, nuclear NF-kappa B p65 expression and DNA-binding activity, endothelial leukocyte adhesion molecule-1 (E-selectin) and intercellular adhesion molecule-1 expression, myeloperoxidase activity, and histologic damages in lung tissues. We also measured serum HDL cholesterol level. RESULTS: 4F improved survival in endotoxemic rats. 4F restored LPS-induced diminution of serum HDL cholesterol level and increased lung S1P(1) expression and phosphorylated Akt/Akt ratio in LPS-treated rats. Furthermore, 4F suppressed inhibitor kappa B-alpha degradation, NF-kappa B activation, E-selectin and intercellular adhesion molecule-1 expression, and myeloperoxidase activity, and attenuated histologic damages in lung tissues. CONCLUSIONS: 4F attenuated acute lung injury and improved survival in endotoxemic rats. The therapeutic benefits of 4F were found to be associated with the stimulation of S1P(1), the activation of Akt, the down-regulation of the NF-kappa B pathway, and the suppression of cell adhesion molecules. (J Trauma Acute Care Surg. 2012;72: 1576Y1583. Copyright (C) 2012 by Lippincott Williams & Wilkins)