The New Vitamin E Derivative, ETS-GS, Protects Against Cecal Ligation and Puncture-Induced Systemic Inflammation in Rats

• Published in: Inflammation Vol. 35; no. 2; pp. 545 - 553
• Main Authors: Koga, Hironori, Hagiwara, Satoshi, Inomata, Masafumi, Kono, Youhei, Oyama, Yoshimasa, Kai, Shinya, Nishida, Taichi, Noguchi, Takayuki
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2012; Springer Nature B.V
• Subjects: Acute Lung Injury - drug therapy; Acute Lung Injury - prevention & control; Animals; Biomedical and Life Sciences; Biomedicine; Cecum - injuries; Cell Line; Edema - drug therapy; Edema - immunology; HMGB1 Protein - blood; I-kappa B Proteins - metabolism; Immunology; Interleukin-6 - blood; Internal Medicine; Leukocytes - immunology; Lung - immunology; Lung - pathology; Macrophages - immunology; Male; Mice; Mitogen-Activated Protein Kinases - metabolism; NF-KappaB Inhibitor alpha; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Pathology; Pharmacology/Toxicology; Phosphatidylinositol 3-Kinase - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism; Random Allocation; Rats; Rats, Wistar; Rheumatology; Sepsis - drug therapy; Sepsis - immunology; Shock, Septic - drug therapy; Shock, Septic - prevention & control; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - immunology; Tumor Necrosis Factor-alpha - blood; lung; acute inflammation; MAPK; sepsis; vitamin E
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-011-9344-2

Sepsis-related systemic inflammation frequently occurs in the critical care setting. Systemic inflammation is implicated in the progression of organ injury, which is associated with a high mortality rate. Recently, vitamin E and glutamic acid have been reported to attenuate inflammation. We therefore investigated whether the vitamin E derivative, ETS-GS, could inhibit the secretion of cytokines and high-mobility group box 1 (HMGB1), and thereby reduce organ damage in a rat model of cecal ligation and puncture (CLP)-induced sepsis. Male Wistar rats weighing 250–300 g were used. Rats received water or ETS-GS (10 mg/kg) by oral administration for 3 weeks, and then sepsis was induced by CLP under sevoflurane anesthesia. Serum levels of interleukin-6, tumor necrosis factor-α, and HMGB1 were determined at 3, 6, and 12 h after CLP; lung histology was assessed at 12 h. Histology results showed markedly reduced interstitial edema and leukocytic infiltration in lung tissue harvested at 12 h in ETS-GS-treated mice compared with untreated controls. ETS-GS treatment also attenuated the CLP-induced increase in serum levels of cytokines and HMGB1. To investigate the mechanisms by which ETS-GS exerts its anti-inflammatory effects, the phosphorylation of Akt, IκBα, and mitogen-activated protein kinase (MAPK) was assessed in mouse macrophage RAW264.7 cells stimulated with LPS, with and without ETS-GS. In these in vitro studies, ETS-GS-induced phosphoinositide 3-kinase (PI3K)–Akt phosphorylation and inhibited IκBα and MAPK phosphorylation. ETS-GS blocked the CLP-induced septic shock response and protected against acute lung injury. This mechanism appeared to be mediated by the induction of PI3K–Akt and the inhibition of IκBα and MAPK phosphorylation. Given these results, ETS-GS shows promise as a potential therapeutic agent for sepsis.