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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Background: The increased prevalence of asthma and allergic diseases in westernized societies has been associated with increased intake of diets rich in n-6 fatty acids (FAs) and poor in n-3 FAs. This study aimed to analyze the prophylactic effects of treatment with a soybean oil-rich diet (rich in n-6) or fish oil (rich in n-3) in an allergic airway inflammation model on lung inflammation score, leukocyte migration, T-helper cell (Th)-2 (interleukin [IL]-4, IL-5) and Th1 (interferon [IFN]-gamma, tumor necrosis factor-alpha) cytokines, lipoxin A4, nitric oxide, bradykinin, and corticosterone levels in bronchoalveolar lavage (BAL) or lungs. Methods: Male Wistar rats fed with soybean oil-or fish oil-rich diet or standard rat chow were sensitized twice with ovalbumin-alumen and challenged twice with ovalbumin aerosol. The BAL and lungs were examined 24 hours later. Results: Both diets, rich in n-6 or n-3 FAs, impaired the allergic lung inflammation and reduced leukocyte migration, eosinophil and neutrophil percentages, and IL-4/IL-5/bradykinin levels in BAL and/or lungs, as well as increased the nitric oxide levels in BAL. The soybean oil-rich diet additionally increased the levels of lipoxin A4 and corticosterone in the lungs. Conclusion: Data presented demonstrated that the n-6 FA-rich diet had protective effect upon allergic airway inflammation and was as anti-inflammatory as the n-3 FA-rich diet, although through different mechanisms, suggesting that both diets could be considered as complementary therapy or a prophylactic alternative for allergic airway inflammation. Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, Brazil Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, Brazil Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil Departamento de Ciências Biológicas, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil FAPESP: 2006/57075-9 CNPq: 302213/2010-4 Web of Science

Objective High-fat diets have been shown to be a risk factor for ulcerative colitis (UC). Omega-6 polyunsaturated fatty acids are considered to increase lipid peroxidation, while the omega-3 polyunsaturated fatty acid exerts a chemopreventative effect. We evaluated the effect of high-fat diets (20%) enriched with fish or soybean oil on colonic inflammation and DNA damage in dextran sulfate sodium-induced colitis. Methods Male Wistar rats (28–30 days) were fed an American Institute of Nutrition (AIN)-93 diet for 47 days and divided into five groups: control normal fat non-colitic (C) or control colitis (CC), high soybean fat group (HS) colitis, high fish fat group colitis, or high-fat soybean plus fish oil colitis. UC was induced from day 35 until day 41 by 3% dextran sulfate sodium. On day 47, the rats were anesthetized; blood samples collected for corticosterone determination, and the distal colon was excised to quantify interleukin-4 (IL-4), IL-10, and interferon-gamma levels, myeloperoxidase activity, histological analyses, and DNA damage. The disease activity index was recorded daily. Results The disease activity index, histological analysis, myeloperoxidase activity, IL-4, interferon-gamma, and corticosterone levels did not differ among the colitic groups. IL-10 was significantly increased by the high fish fat group diet in relation to HS, but only the high soybean-fish fat diet increased the IL-10/IL-4 ratio (anti-inflammatory/pro-inflammatory) to levels closer to the C group and reduced DNA damage compared to the HS group ( P Conclusion The data show that high-fat diets did not exacerbate UC and suggest that the soybean and fish oil mixture, more than the fish oil alone, could be a complementary therapy to achieve a cytokine balance in UC.

Previously, we have shown that electroacupuncture (EA) in rats decreased eosinophil infiltration into the pulmonary tissue (PT) and in the bronchoalveolar lavage (BAL) in an experimental model of asthma. Th2 cytokines, leukotriene B4 (LTB4) and nitric oxide (NO) are involved in the asthma inflammatory process. The aim of this study was to verify the effects of EA on these asthma mediators. Male Wistar rats were divided into control (C), immobilized (I), sham acupuncture (SA), and acupuncture (A) groups. All rats were sensitized, and EA treatment using clinical acupuncture points was started 24 h after antigen priming. EA was done every other day for 2 weeks. Subsequently, animals were challenged by inhalation and sacrificed 24 h later. At this time, the BAL and lungs were collected and used to analyze cytokine production, LTB4 and NO. The EA increased IL-1 and IFN-γ and decreased IL-4, IL-10, NO and LTB4 in the BAL and PT compared to the C and SA groups. The presence of eosinophils in the BAL negatively correlated with IL-1 and IFN-γ production and positively correlated with IL-4 and IL-10 production. Our results show that the beneficial anti-inflammatory action of EA on asthma is related to the balance of the Thl/Th2 response and the reduction of LTB4 and NO. These results suggest that EA therapy could be an important complementary treatment for asthma.

We have previously demonstrated that both n-3 and n-6 polyunsaturated fatty acids (PUFA)-rich diets decrease the acute inflammatory response partially explained by the high corticosterone basal levels. The present study aimed to determine the effect of hyperlipidic diets (PUFA n-3 or n-6) on phagocytosis, hydrogen peroxide (H(2)O(2)) and nitric oxide (NO) release by macrophages, bradykinin (BK) and NO release in the paw inflammatory perfusate and Kallikrein (KK), corticosterone and leptin blood levels. Hyperlipidic diets decreased H(2)O(2) release from macrophages stimulated by carrageenan or phorbol-miristate-acetate (PMA), NO release from macrophage stimulated by carrageenan, BK and NO release in the edema perfusate, KK plasma levels and the increase of serum leptin after carrageenan stimulus. These data show that both fish and soybean oil-rich diets promote similar alterations on inflammatory mediators of carrageenan edema and a causal association with the anti-inflammatory effect of these diets.

We have previously shown that both n-3 (fish oil) and n-6 (soybean oil) PUFA-rich diets reduce carrageenan-induced paw edema in rats. The present study evaluated the role of corticosteroids, and the effect of indomethacin on this response. Basal (pre-carrageenan) levels of corticosterone were elevated in both lipid diets compared to the chow diet. During inflammation, corticosterone levels increased to a similar extent in the chow and lipid diets. With 2.0 mg/kg indomethacin, edema was reduced in the chow diet and the n-3 diet, while it was not changed in the n-6 diet. In contrast, the 16.6 mg/kg dose of indomethacin induced a mild increase in edema in the chow diet but a pronounced edema increase in the lipid diets. The increase in corticosterone levels induced by carrageenan was either reduced (chow) or completely abolished (lipids) by the treatment with the higher dose of indomethacin, compared to both the control (untreated) group, and the lower dose of indomethacin. These data indicate that both acute inflammation and the response to an antiinflammatory drug were attenuated by n-3 or n-6 PUFA-rich diets. They also showed that indomethacin can have anti- or proinflammatory properties reflecting the extent of the corticosterone inhibition by indomethacin.

Eicosanoids (prostaglandins, leukotrienes and lipoxins) are signaling lipids derived from arachidonic acid metabolism that have important roles in physiological and pathological processes. Lately, intracellular compartmentalization of eicosanoid-synthetic machinery has emerged as a key component in the regulation of eicosanoid synthesis and functions. Over the past years substantial progresses have been made demonstrating that precursors and enzymes involved in eicosanoid synthesis localize at lipid bodies (also known as lipid droplets) and lipid bodies are distinct sites for eicosanoid generation. Here we will review the current knowledge on the functions of lipid bodies as specialized intracellular sites of compartmentalization of signaling with major roles in eicosanoid formation within cells engaged in inflammatory, infectious and neoplastic process.

It was investigated whether dietary polyunsaturated fatty acids (PUFA) could influence colonic injury, tissue DNA damage, cytokines and myeloperoxidase activity (MPO) and plasma corticosterone in DSS-induced colitis rats. Male weaning Wistar rats were fed for 47 days with an AIN-93 diet with control (C), fish (F) or a mixture of fish and soybean oil (SF). The colitis was induced from day 36 until day 42 by 3% DSS in drinking water. On day 48, blood samples were collected for corticosterone determination. The distal colon was excised for histological analysis and to quantify the cytokine (IL-4, IL-10 and INF-γ), MPO and DNA damage. The disease activity index (DAI) was recorded daily during colitis induction. The DAI, MPO, histological analyses showed decreases only in the SF group compared with the C group. IL-10 was increased and DNA damage was reduced in the groups F and SF, and an inverse correlation between these variables was found. There were no differences in corticosterone, IFN-γ and IL-4 levels. Soybean and fish oil mixture may be effective in improving colonic injury and DNA damage, and it could be an important complementary therapy in UC to reduce the use of anti-inflammatory drugs and prevent colorectal cancer.

Wellcome Trust Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Medical Research Council/Glaxo SmithKline Pilot Industry Award As our understanding of inflammatory resolution increases, drugs that trigger proresolution pathways may become significant in treating chronic inflammatory diseases. However, anti-inflammatory drugs are traditionally tested during the first hours of onset (i.e., to dampen leukocyte and edema formation), and their ability to trigger proresolution processes has never been investigated. Moreover, there is no model available to screen for putative proresolving agents. in this study, we present a new strategy to identify therapeutics for their ability to switch inflammation off and restore homeostasis. Injecting 1.0 mg of zymosan i.p. causes transient inflammation characterized by polymorphonuclear neutrophil clearance and dominated by recently described resolution-phase macrophages along with an innate-type lymphocyte repopulation, the latter being a marker of tissue homeostasis. in contrast, 10 mg of zymosan elicits an aggressive response characterized by classically activated macrophages leading to systemic inflammation and impaired lymphocyte repopulation. Although this latter model eventually resolves, it nonetheless represents inflammation in the clinically relevant setting of polymorphonuclear neutrophil/classically activated macrophage dominance driving a cytokine storm. Treating such a reaction therapeutically with proresolution drugs provides quantifiable indices of resolution-polymorphonuclear neutrophil/macrophage clearance, macrophage phenotype switching (classically activated to resolution phase), and repopulation with resolution-phase lymphocytes-cardinal signs of inflammatory resolution and homeostasis in the peritoneum. As an illustration, mice bearing peritonitis induced by 10 mg of zymosan- were given ibuprofen, resolvin El, a prostaglandin D(2) receptor 1 agonist, dexamethasone, rolipram, or azithromycin, and their ability to trigger resolution and homeostasis in this new inflammatory setting was investigated. We present the first model for testing drugs with targeted proresolution properties using quantifiable parameters of inflammatory resolution and homeostasis. the Journal of Immunology, 2010, 184: 1516-1525. UCL, Rayne Inst, Div Med, Ctr Clin Pharmacol & Therapeut, London WC1E 6JJ, England GlaxoSmithKline Inc, Resp CEDD, Stevenage, Herts, England Universidade Federal de São Paulo, Dept Physiol, São Paulo, Brazil Universidade Federal de São Paulo, Dept Physiol, São Paulo, Brazil Web of Science