γ-Tocopherol Nebulization Decreases Oxidative Stress, Arginase Activity, and Collagen Deposition After Burn and Smoke Inhalation in the Ovine Model.
*Departments of Anesthesiology and Pathology, University of Texas Medical Branch, Galveston, TexasShock (Augusta, Ga.) (Impact Factor: 3.05). 12/2012; 38(6):671-6. DOI: 10.1097/SHK.0b013e3182758759
More than 20,000 burn injury victims suffer from smoke inhalation injury in the United States annually. In an ovine model of acute lung injury, γ-tocopherol had a beneficial effect when nebulized into the airway. We hypothesize that γ-tocopherol scavenges reactive oxygen species (ROS) and reactive nitrogen species resulting from burn and smoke inhalation injury and that these ROS/reactive nitrogen species activate the arginase pathway, leading to increased collagen deposition and decreased pulmonary function. To test this hypothesis, ewes were operatively prepared for chronic study, then they were randomly divided into groups (n = 8): uninjured, injured, or injured with nebulization (γ-tocopherol [950 mg/g] and α-tocopherol [40 mg/g] from hours 3 to 48 after the injury). The injury, under deep anesthesia, consisted of a 20% total body surface burn and 36 breaths of cotton smoke; all animals were killed after 3 weeks. Treatment increased lung γ-tocopherol at 3 weeks after γ-tocopherol nebulization compared with injured sheep (1.75 ± 0.62 nmol/g vs. 0.45 ± 0.06, P < 0.05). The expression of dimethylarginine dimethylaminohydrolase-2, which degrades asymmetrical dimethylarginine, a nitric oxide synthase inhibitor, significantly increases with γ-tocopherol treatment compared with injured sheep (P < 0.05). Arginase activity (0.15 ± 0.02 μM urea/μg protein vs. 0.24 ± 0.009, P < 0.05), ornithine aminotransferase (11,720 ± 888 vs. 13,170 ± 1,775), and collagen deposition (0.62 ± 0.12 μM hydroxyproline/μg protein vs. 1.02 ± 0.13, P < 0.05) significantly decrease with γ-tocopherol compared with injured animals without γ-tocopherol. The decreases in arginase and collagen with γ-tocopherol are associated with significantly increased diffusion capacity (P < 0.05) and decreased lung wet-to-dry ratio (P < 0.05). Smoke-induced chronic pulmonary dysfunction is mediated through the ROS/asymmetrical dimethylarginine/arginase pathway, and ROS scavengers such as γ-tocopherol may be a potential therapeutic management of burn patients with inhalation injury.
Article: What's new in Shock? December 2012
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ABSTRACT: The Vitamin E family consists of four tocopherols and four tocotrienols. α-Tocopherol (αT) is the predominant form of vitamin E in tissues and its deficiency leads to ataxia in humans. However, results from many clinical studies do not support protective roles of αT in disease prevention in people with adequate nutrient status. On the other hand, recent mechanistic studies indicate that other forms of vitamin E such as γ-tocopherol (γT), δ-tocopherol (δT) and γ-tocotrienol (γTE) have unique antioxidant and anti-inflammatory properties that are superior to αT in prevention and therapy against chronic diseases. These vitamin E forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress pro-inflammatory signaling such as NF-κB and STAT3/6. Unlike αT, other vitamin E forms are significantly metabolized to carboxychromanols via cytochrome P-450 (CYP4F2)-initiated side-chain ω-oxidation. Long-chain carboxychromanols, esp.13'-carboxychromanols, are shown to have stronger anti-inflammatory effects than un-metabolized vitamins and may therefore contribute to beneficial effects of vitamin E forms in vivo. Consistent with mechanistic findings, animal and human studies show that γT and tocotrienols may be useful against inflammation-associated diseases. This review focuses on non-αT forms of vitamin E with respect to their metabolism, anti-inflammatory effects and mechanisms and in vivo efficacy in preclinical models as well as human clinical intervention studies.
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ABSTRACT: Purpose Valproate (VPA) induced hyperammonemia (VHA) and hyperammonemic encephalopathy (VHE) are well-known phenomenon's related to VPA treatment. Risk factors for VHE are high VPA dosage, need of poly-therapy medication and long duration of treatment Despite a severe nature of the epilepsy, presence of concomitant psychiatric manifestations, and need for poly-pharmacy, occurrence of VHA/VHE in juvenile ceroid lipofuscinosis (JNCL, Batten disease) or other subtypes of neuronal ceroid lipofuscinosis have not previously been reported in the literature. The aim of the present publication is to describe four cases with VHE in a well-defined Danish population of JNCL. Method An examination of medical records of all 35 patients with JNCL in Denmark was conducted and revealed fourteen patients treated with VPA. Results Four patients treated with VPA developed VHE. All patients were prescribed VPA in standard dosages, had normal plasma concentrations of VPA and received poly-therapy. Symptoms occurred shortly after commencement or increase in dose of VPA, and were quickly reversible upon discontinuation of VPA. Carnitine supplement was administrated in two patients, which resulted in resolution of symptoms and normalized ammonium levels. Conclusion Patients with JNCL are in great risk of developing VHA and VHE due to a high rate of poly-pharmacy. Furthermore, studies have shown that carnitine level can be depressed in JNCL, which may increase the risk of VHA and VHE. We recommend that increased attention should be given to these patients.
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