title: The induction of super-resistance using synthetic lipopolysaccharide receptor agonist rescues fatal endotoxemia in rats without excessive immunosuppression.
abstract: Endotoxin tolerance provides protection against mortality under various conditions of stress. However, the induction of endotoxin tolerance thus far has no clinical application because of endotoxin toxicity and the excessive immune suppression that follows the tolerance induction. In this study, we examined whether a novel, synthetic lipopolysaccharide (LPS) receptor agonist, ER-803058 (ER) can induce endotoxin tolerance with accompanying low toxicity. The stimulative effects of ER on tumor necrosis factor (TNF)-alpha production from RAW264 cells were 50% to 70% lower than those of the corresponding quantities of LPS. ER pretreatment also diminished TNF-alpha secretion induced by a subsequent LPS shock. However, the degree of desensitization with ER pretreatment (10 ng/mL, 55.5% +/- 6.7%; 100 ng/mL, 42.3 +/- 4.9%) was modest in contrast with that measured for the corresponding LPS pretreatment (10 ng/mL, 36.7% +/- 3.7%; 100 ng/mL, 20.0% +/- 3.6%). The minimum in vivo dose (0.02 mg/kg/body weight) of ER-induced negligible production of TNF-alpha and interleukin (IL)-6 in rats, and resulted in a modest endotoxin tolerance with respect to TNF-alpha secretion. Although the plasma TNF-alpha level after ER pretreatment was decreased (48.2% +/- 1.1%), the suppression was not statistically significant. Interestingly, even this minimal quantity of ER pretreatment evoked a dramatic improvement in survival (90% survival) against administration of a lethal dose of LPS, which is inconsistent with the modest TNF-alpha suppression. Furthermore, ER pretreatment preserved normal plasma albumin levels and prevented the increase of plasma blood urea nitrogen levels seen with LPS. These results indicate that pretreatment with ER can effectively induce endotoxin tolerance, with a consequent improvement in mortality without toxicity and without subsequent excessive immunosuppression.
authors.affiliation: Department of Metabolic Care and Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hatao
authors.forename: Naoki
authors.initials: N
authors.lastname: Hiki
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Mimura
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ogawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kojima
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Mafune
authors.forename: Lynn D
authors.initials: LD
authors.lastname: Hawkins
authors.forename: Masashi
authors.initials: M
authors.lastname: Muroi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Tanamoto
authors.forename: Michio
authors.initials: M
authors.lastname: Kaminishi
mesh_terms: D000418:Albumins / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D001806:Blood Urea Nitrogen; D001835:Body Weight; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000188:drug therapy*; D004731:Endotoxins / Q000378:metabolism / Q000633:toxicity*; D007107:Immune System / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000418:Albumins; D016207:Cytokines; D004731:Endotoxins; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma