linoleic-acid and Burns

It has been claimed that lipid emulsions with a restricted linoleic acid content can improve the safety of total parenteral nutrition (TPN). The tolerability of TPN and its effects on the metabolism of fatty acids were assessed in this prospective, double-blind, randomised study comparing an olive/soyabean oil long-chain triacylglycerol (LCT) with a medium-chain triacylglycerol (MCT)/LCT; 50:50 (w) based lipid emulsion in two groups (O and M, respectively; eleven per group) of severely burned patients. After resuscitation (48-72 h), patients received TPN providing 147 kJ/kg per d (35 kcal/kg per d) with fat (1.3 g/kg per d) for 6 d Plasma fatty acids, laboratory parameters including liver function tests, and plasma cytokines were assessed before and after TPN. Adverse events encountered during TPN and the clinical outcomes of patients within the subsequent 6 months were recorded. With both lipid emulsions, the conversion of linoleic acid in its higher derivatives (di-homo-gamma-linolenic acid) improved and essential fatty acid deficiency did not appear. Abnormalities of liver function tests occurred more frequently in the M (nine) than in the O (three) group (P = 0.04, Suissa-Shuster test). Seven patients (four from group O and three from group M) died as a consequence of severe sepsis 3-37 d after completion of the 6 d TPN period. When compared with the surviving patients, those who died were older (P = 0.01) and hyperglycaemic at baseline (P < 0.001), and their plasma IL-6 levels continued to increase (P < 0.04). Although fatty acid metabolism and TPN tolerability were similar with both lipid emulsions, the preservation of liver function noted with the use of the olive oil-based lipid emulsions deserves confirmation.

Topics: Adult; Blood Glucose; Burns; Cholesterol; Double-Blind Method; Fat Emulsions, Intravenous; Fatty Acids; Female; Humans; Linoleic Acid; Liver Function Tests; Male; Middle Aged; Olive Oil; Parenteral Nutrition, Total; Phospholipids; Plant Oils; Prospective Studies; Triglycerides

Fatty acid composition in the Western diet has shifted from saturated to polyunsaturated fatty acids (PUFAs), and specifically to linoleic acid (LA, 18:2), which has gradually increased in the diet over the past 50 y to become the most abundant dietary fatty acid in human adipose tissue. PUFA-derived oxylipins regulate a variety of biological functions. The cytochrome P450 (CYP450)–formed epoxy fatty acid metabolites of LA (EpOMEs) are hydrolyzed by the soluble epoxide hydrolase enzyme (sEH) to dihydroxyoctadecenoic acids (DiHOMEs). DiHOMEs are considered cardioprotective at low concentrations but at higher levels have been implicated as vascular permeability and cytotoxic agents and are associated with acute respiratory distress syndrome in severe COVID-19 patients. High EpOME levels have also correlated with sepsis-related fatalities; however, those studies failed to monitor DiHOME levels. Considering the overlap of burn pathophysiology with these pathologies, the role of DiHOMEs in the immune response to burn injury was investigated. 12,13-DiHOME was found to facilitate the maturation and activation of stimulated neutrophils, while impeding monocyte and macrophage functionality and cytokine generation. In addition, DiHOME serum concentrations were significantly elevated in burn-injured mice and these increases were ablated by administration of 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a sEH inhibitor. TPPU also reduced necrosis of innate and adaptive immune cells in burned mice, in a dose-dependent manner. The findings suggest DiHOMEs are a key driver of immune cell dysfunction in severe burn injury through hyperinflammatory neutrophilic and impaired monocytic actions, and inhibition of sEH might be a promising therapeutic strategy to mitigate deleterious outcomes in burn patients.

Topics: Animals; Burns; Epoxide Hydrolases; Humans; Immunity, Innate; Inflammation; Linoleic Acid; Mice; Mice, Inbred C57BL; Phenylurea Compounds; Piperidines; Sepsis

The primary complaint of burn victims is an intense, often devastating spontaneous pain, with persistence of mechanical and thermal allodynia. The transient receptor potential channels, TRPV1 and TRPA1, are expressed by a subset of nociceptive sensory neurons and contribute to inflammatory hypersensitivity. Although their function in the periphery is well known, a role for these TRP channels in central pain mechanisms is less well defined. Lipid agonists of TRPV1 are released from peripheral tissues via enzymatic oxidation after burn injury; however, it is not known if burn injury triggers the release of oxidized lipids in the spinal cord. Accordingly, we evaluated whether burn injury evoked the central release of oxidized lipids . Analysis of lipid extracts of spinal cord tissue with HPLC-MS revealed a significant increase in levels of the epoxide and diol metabolites of linoleic acid: 9,10-DiHOME, 12,13-DiHOME, 9(10)-EpOME, and 12(13)-EpOME, that was reduced after intrathecal (i.t.) injection of the oxidative enzyme inhibitor ketoconazole. Moreover, we found that these four lipid metabolites were capable of specifically activating both TRPV1 and TRPA1. Intrathecal injection of specific antagonists to TRPV1 (AMG-517) or TRPA1 (HC-030031) significantly reduced post-burn mechanical and thermal allodynia. Finally, i.t. injection of ketoconazole significantly reversed post-burn mechanical and thermal allodynia. Our data indicate that spinal cord TRPV1 and TRPA1 contributes to pain after burn and identifies a novel class of oxidized lipids elevated in the spinal cord after burn injury. Since the management of burn pain is problematic, these findings point to a novel approach for treating post-burn pain.

Topics: Animals; Burns; CHO Cells; Cricetinae; Cricetulus; Hyperalgesia; Ion Channel Gating; Linoleic Acid; Male; Oxidation-Reduction; Rats, Sprague-Dawley; Sensory Receptor Cells; Spinal Cord; Time Factors; TRPA1 Cation Channel; TRPC Cation Channels; TRPV Cation Channels

Oxidized linoleic acid metabolites (OLAMs) are a class of endogenous transient receptor potential vanilloid 1 (TRPV1) channel agonists released on exposure of tissue to transient noxious temperatures. These lipid compounds also contribute to inflammatory and heat allodynia. Because persistent pain after a burn injury represents a significant clinical challenge for treatment, we developed an in vivo rat model of partial-thickness cutaneous thermal injury and examined whether TRPV1 and specific OLAM metabolites play a role in mediating postburn pain injury. This peripheral model of burn injury had marked thermal allodynia peaking at 24h after thermal injury, with allodynia being maintained for up to 7d. Immunohistochemical characterization of tissue taken from injury sites revealed an increase in leukocyte/macrophage infiltration that was colocalized with TRPV1-positive fibers. Using this peripheral thermal injury model, we found that pharmacological blockade of peripheral TRPV1 receptors reduced thermal allodynia by about 98%. Moreover, there was a significant increase in OLAM levels compared to naive controls in hind paw skin biopsies. Additional studies of the metabolism of [C(14)]-linoleic acid in skin biopsies revealed the role of the cytochrome P450 (CYP) system in mediating the metabolism of linoleic acid after thermal injury. Finally, we demonstrated that direct inhibition of OLAMs using OLAM antibodies and indirect inhibition using the CYP inhibitor ketoconazole significantly reduced postburn thermal allodynia. Collectively, these findings point to a novel role of the OLAMs and CYP-related enzymes in generating postburn allodynia via activation of peripheral TRPV1.

Topics: Animals; Behavior, Animal; Benzothiazoles; Burns; Chromatography, High Pressure Liquid; Hot Temperature; Hyperalgesia; Immunohistochemistry; Ketoconazole; Linoleic Acid; Lipids; Male; Nerve Fibers; Neutrophil Infiltration; Oxidation-Reduction; Pain; Pain Measurement; Pyrimidines; Rats; Rats, Sprague-Dawley; Skin; TRPV Cation Channels

The objective of this study was to examine compositional and quantitative changes in fatty acids of plasma components and red blood cell phospholipids (PL) immediately following and during recovery from burn injury. Subjects (n = 10) with >10% total body surface area burn had blood drawn at specific timepoints (0 to >50 d) following burn injury. Fatty acid composition of red blood cell PL and plasma PL, cholesteryl esters (CE), and triglycerides was determined using gas-liquid chromatography after separating each fraction from extracted lipids by thin-layer chromatography. Total plasma PL and CE in burn patients were lower than in healthy control subjects with reduced 20:4n-6, n-6, and n-3 fatty acids and higher levels of monounsaturated and saturated fatty acids early after burn. CE levels remained half that of healthy control values up to 50 d post-burn. Red blood cell PL had decreased 20:4n-6 content and profiles similar to that of an essential fatty acid deficiency early after burn. These results suggest an impairment in lipoprotein and polyunsaturated fatty acid metabolism in the early post-burn period. Lower levels of 20:4n-6 and n-3 fatty acids in every plasma fraction suggest increased use of these fatty acids for wound healing and immune function following burn injury. Further work is needed to determine the ability of burn patients to utilize essential fatty acids in order to design nutritional intervention that promotes wound healing and immunological functions consistent with recovery in these patients.

Topics: Adult; Aged; alpha-Linolenic Acid; Burns; Cholesterol Esters; Dietary Fats; Energy Intake; Enteral Nutrition; Erythrocytes; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Humans; Linoleic Acid; Lipids; Male; Middle Aged; Phospholipids; Triglycerides

The effects of different types of dietary lipids were tested in burned guinea pigs. All diets were identical except for the type of lipid, with total energy intake from lipids equaling 10%. All animals received a 30% total body surface area (TBSA) flame burn and were fed identically by pump-controlled gastrostomy feedings for 14 days. When compared to safflower oil (74% linoleic acid) as well as linoleic acid alone, fish oil (18% eicosapentaenoic acid or EPA) administration resulted in less weight loss, better skeletal muscle mass, lower resting metabolic expenditure, better cell mediated immune responses, better opsonic indices, higher splenic weight, lower adrenal weight, higher serum transferrin, and lower serum C3 levels. With the exception of better cell mediated immune responses in the animals fed linoleic acid, the administration of indomethacin made little difference. These findings can be explained by a reduction in the synthesis of the dienoic prostaglandins that are derived from the omega 6 series of fatty acids, some of which are significantly immunosuppressive. Regulation of dietary lipids may be an important therapeutic advance in nutritional support after burn injury, and controlled trials should be considered.

Topics: Animals; Body Weight; Burns; Complement C3; Dietary Fats; Dinoprostone; Eicosapentaenoic Acid; Energy Metabolism; Female; Guinea Pigs; Immunity, Cellular; Indomethacin; Linoleic Acid; Linoleic Acids; Macrophages; Nitrogen; Organ Size; Phagocytosis; Prostaglandins E; Transferrin