Delayed Administration of D-Ala2-D-Leu5-Enkephalin, a Delta-Opioid Receptor Agonist, Improves Survival in a Rat Model of Sepsis
スポンサーリンク
概要
- 論文の詳細を見る
Sepsis is the major cause of death in intensive care units, despite enormous efforts in the development of antimicrobial therapies. Sepsis is mediated by early [e.g., tumor necrosis factor (TNF)-α and interleukin (IL)-1β] and late [e.g., high-mobility group box 1 protein (HMGB1)] proinflammatory cytokines. HMGB1, which is secreted into extracellular milieu by activated macrophages or passively released by destroyed macrophages, stimulates intensive inflammatory responses. D-Ala2-D-Leu5-enkephalin (DADLE), a synthetic δ-opioid receptor agonist, has been shown to protect rats from sepsis. Here we elucidated the mechanism for protective effect of DADLE against sepsis. Sepsis was established in Sprague-Dawley rats by means of cecal ligation and puncture (CLP). In this model, the serum levels of TNF-α and IL-1β were increased after 2-3 h, while those of HMGB1 were increased after 18 h. Administration of DADLE (5 mg/kg) concurrently with CLP improved survival, which was associated with the decreases in the serum levels of TNF-α, IL-1β and HMGB1. Importantly, DADLE administrated 4 h after CLP showed comparable protective effect as the concurrent administration, with decreased serum HMGB1 levels. Moreover, peritoneal macrophages isolated from rats were challenged with lipopolysaccharide (LPS). Concurrent or delayed DADLE administration at 10−6 M suppressed the LPS-induced cell death. DADLE also suppressed the release of HMGB1 from macrophages that was induced by LPS, TNF-α or interferon-γ. In conclusion, DADLE protects rats from sepsis probably by decreasing the serum level of HMGB1. We propose DADLE as a candidate for septic shock therapy, even if it is administered after the onset of sepsis.
- 東北ジャーナル刊行会の論文
東北ジャーナル刊行会 | 論文
- Effects of Ketamine and Propofol on the Ratio of Interleukin-6 to Interleukin-10 during Endotoxemia in Rats
- α2-Adrenergic Modulation of Glucagon and Insulin Secretions in Sheep
- Molecular Analysis of the Pathogenesis of Autoimmune Insulitis in NOD Mice
- Effects of Thymoxamine in Ouabain-Induced Arrhythmias in Dogs
- T Cell Hypofunctions and Glomerular Sclerotic and Angiogenic Changes Found Both in Rats Received Unilateral Nephrectomy plus Transplantation of Syngeneic Mesenteric Lymph Nodes and in Rats Received Unilateral Nephrectomy plus Splenectomy