8-11-14-eicosatrienoic-acid and Fever

Until recently, studies on the role of the metabolites of arachidonic acid (AA), eicosanoids in fever have primarily focused on prostaglandins, prostaglandin E2 (PGE2) in particular, derived from the pathway related to cyclooxygenases (COX). COX exists in two known isoforms; a constitutive COX-1, and COX-2, which is inducible upon the action of pyrogens. Data accumulated in our laboratories suggest a thermoregulatory role for two other pathways of arachidonate metabolism; 5-lipoxygenase (5-LOX) and cytochrome P-450 (epoxygenase). We have demonstrated that leukotrienes (LTs; 5-LOX-derived eicosanoids) and various isomers of epoxyeicosatrienoic acids (EETs; epoxygenase-derived eicosanoids) contribute to the process of endogenous antipyresis or cryogenesis, which limits the height of fever. In support of this are several lines of evidence based on both in vivo and in vitro experiments. 1) Intracerebroventricular (icv) injections of LTC4 at nanomolar concentrations cause a dose-dependent decrease of body temperature (Tb) in mice. 2) Lipopolysaccharide (LPS)-induced anapyrexia in mice is preceded and accompanied by elevation in hypothalamic cysteinyl-LT (CysLT) production. 3) The inhibitor of LT synthesis MK-886 suppresses both of these processes. 4) EETs as well as inducers of the epoxygenase attenuate, whereas inhibitors of epoxygenase enhance the LPS-induced fever in rats. 5) One of the isomers of EET, 11,12-EET, in in vitro studies inhibited both the generation of PGE2 and IL-6 in monocytes stimulated with LPS. These results, together with a well-established pyrogenic role of PGE2, indicate that AA cascade may be regarded as an endogenous system to regulate the temperature response upon disease. COX, 5-LOX, and epoxygenase products may act at the level of hypothalamus as proximal mediators of, respectively, fever (PGE2) or cryogenesis (CysLTs and EETs), or indirectly by influencing the other endogenous cryogens and pyrogens.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 5-Lipoxygenase; Body Temperature; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Eicosanoids; Feedback, Physiological; Fever; Humans; Hypothalamus; Indoles; Inflammation; Leukotrienes; Lipopolysaccharides; Macrophages; Mice; Protein Isoforms; Rats

PUFA might modulate inflammatory responses involved in the development of severe dengue. We aimed to examine whether serum PUFA concentrations in patients diagnosed with dengue fever (DF) were related to the risk of progression to dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). A secondary aim was to assess correlations between fatty acids (FA) and inflammatory biomarkers in patients with DF. We conducted a prospective case-control study nested within a cohort of patients who were diagnosed with DF and followed during the acute episode. We compared the distribution of individual FA (% of total FA) at onset of fever between 109 cases who progressed to DHF/DSS and 235 DF non-progressing controls using unconditional logistic regression. We estimated correlations between baseline FA and cytokine concentrations and compared FA concentrations between the acute episode and >1 year post-convalescence in a subgroup. DHA was positively related to progression to DHF/DSS (multivariable adjusted OR (AOR) for DHA in quintile 5 v. 1=5·34, 95 % CI 2·03, 14·1; P trend=0·007). Dihomo-γ-linolenic acid (DGLA) was inversely associated with progression (AOR for quintile 5 v. 1=0·30, 95 % CI 0·13, 0·69; P trend=0·007). Pentadecanoic acid concentrations were inversely related to DHF/DSS. Correlations of PUFA with cytokines at baseline were low. PUFA were lower during the acute episode than in a disease-free period. In conclusion, serum DHA in patients with DF predicts higher odds of progression to DHF/DSS whereas DGLA and pentadecanoic acid predict lower odds.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Adult; Case-Control Studies; Child; Cytokines; Dengue; Disease Progression; Docosahexaenoic Acids; Fatty Acids; Female; Fever; Hemorrhagic Fevers, Viral; Humans; Inflammation; Logistic Models; Male; Nutritional Status; Odds Ratio; Prospective Studies; Severe Dengue; Severity of Illness Index; Young Adult

Inhibitors of cytochrome P-450 augment fever in rats and mice, indicating that the metabolite of the enzyme is candidate of endogenous antipyretic. Cytochrome P-450 of arachidonic acid cascade leads to the formation of regioisomeric 5,6-, 8,9- 11,12- and 14,15-epoxyeicosatrienoic acid (EET). Various isomers of EET were administrated into the preoptic area and anterior hypothalamus (PO/AH) to test their influence on fever induced by interleukin-1beta (IL-1beta) administrated into the PO/AH in conscious rats. The IL-beta-induced fever was attenuated in the 11,12-EET-pretreated rats, although 5,6-, 8,9- and 14,15-EET did not affect the fever. Intra-PO/AH injection of 11,12-EET did not alter normal body temperature. The results suggest that 11,12-EET acts in the hypothalamus as an endogenous antipyretic.

Topics: 8,11,14-Eicosatrienoic Acid; Analgesics, Non-Narcotic; Animals; Anterior Hypothalamic Nucleus; Arachidonic Acid; Cytochrome P-450 Enzyme System; Fever; Interleukin-1; Male; Preoptic Area; Rats; Rats, Wistar; Vasodilator Agents