title: Delayed administration of D-Ala2-D-Leu5-enkephalin, a delta-opioid receptor agonist, improves survival in a rat model of sepsis.
abstract: 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.
authors.affiliation: Department of Hepatobiliary Surgery and Molecular Surgery, First People's Hospital affiliated to Huzhou University Medical College, PR China.
authors.forename: Cheng Wu
authors.initials: CW
authors.lastname: Tang
authors.forename: Wen Ming
authors.initials: WM
authors.lastname: Feng
authors.forename: Hui Min
authors.initials: HM
authors.lastname: Du
authors.forename: Ying
authors.initials: Y
authors.lastname: Bao
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016308:Enkephalin, Leucine-2-Alanine / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017465:Receptors, Opioid, delta; D014409:Tumor Necrosis Factor-alpha; D016308:Enkephalin, Leucine-2-Alanine; D048051:p38 Mitogen-Activated Protein Kinases