Fatty acids, inflammation, and asthma
2014; Elsevier BV; Volume: 133; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2013.12.1087
ISSN1097-6825
AutoresStacy G. Wendell, Cindy Baffi, Fernando Holguín,
Tópico(s)Inflammatory mediators and NSAID effects
ResumoFatty acids and consequently diet play an essential role in the formation of inflammatory mediators involved in the pathogenesis of asthma. Because intake variations of omega-6 (n-6) and omega-3 (n-3) fatty acids ultimately determine cell membrane incorporation, changes in diet have the potential to modify downstream production of inflammatory mediators derived from these compounds. It has long been hypothesized that decreasing the n-6/n-3 ratio could reduce the production of more proinflammatory mediators while increasing the formation of downstream metabolites that can serve to limit or resolve inflammation. In turn, these changes would result in improved asthma outcomes or would lower the risk for asthma incidence. This review will focus on the role of fatty acid inflammatory and resolving mediators and will summarize the clinical and epidemiologic data on how diet and obesity alter fatty acid profiles that can contribute to asthma. Fatty acids and consequently diet play an essential role in the formation of inflammatory mediators involved in the pathogenesis of asthma. Because intake variations of omega-6 (n-6) and omega-3 (n-3) fatty acids ultimately determine cell membrane incorporation, changes in diet have the potential to modify downstream production of inflammatory mediators derived from these compounds. It has long been hypothesized that decreasing the n-6/n-3 ratio could reduce the production of more proinflammatory mediators while increasing the formation of downstream metabolites that can serve to limit or resolve inflammation. In turn, these changes would result in improved asthma outcomes or would lower the risk for asthma incidence. This review will focus on the role of fatty acid inflammatory and resolving mediators and will summarize the clinical and epidemiologic data on how diet and obesity alter fatty acid profiles that can contribute to asthma. Chronic airway inflammation is coordinated by a complex web of inflammatory mediators, including interleukins, adhesion molecules, inflammatory enzymes, and lipid mediators. Rigorous study in the area of lipid mediators has revealed that these mediators are produced at specific points during the processes of inflammation and resolution. Some lipid mediators promote inflammation, whereas others are made at later stages in the process and promote a return to cellular homeostasis in the resolution phase. When transition to the resolving phase from an inflammatory response to an acute injury does not occur or a state of chronic inflammation manifests, the system is overwhelmed, and negative physiologic consequences occur. Such is the case in asthma, a disease mediated by chronic airway inflammation leading to bronchoconstriction and, potentially, airway remodeling. Most of the lipid mediators that regulate inflammation are metabolites derived from omega-6 (n-6) or omega-3 (n-3) fatty acids, including arachidonic acid (AA; 20:4n-6), linoleic acid (LA; 18:2n-6), eicosapentaenoic acid (EPA; 20:5n-3), and docosahexaenoic acid (DHA; 22:6n-3; Fig 1). Through enzymatic oxidation by COX, lipoxygenase (LO), cytochrome P450 (CYP) enzymes, or reactive oxygen species, oxygenated metabolites are formed, many of which possess biological actions. n-6 fatty acids are generally described as proinflammatory, and n-3 fatty acids are generally described as anti-inflammatory. In general, this is true; however, it has been realized that although a fatty acid mediator might be proinflammatory in one disease or tissue, it can be anti-inflammatory in another, as is the case for the AA-derived prostaglandin (PG) E2. The main AA-derived mediators of inflammation in asthma are PGs and cysteinyl leukotrienes (CysLTs).1Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (2966) Google Scholar, 2Wenzel S.E. Arachidonic acid metabolites: mediators of inflammation in asthma.Pharmacotherapy. 1997; 17: 3S-12SPubMed Google Scholar There are many other eicosanoids that have been implicated; however, their roles remain somewhat controversial compared with PGs and leukotrienes (LTs). Therefore this review will focus only on PGs and LTs as inflammatory mediators. Proresolving fatty acids are formed in response to an inflammatory event and accelerate a return to cellular homeostasis. Most of these are n-3–derived metabolites and include resolvins, protectins, and maresins. The one exception is the lipoxin family, which is derived from AA.3Levy B.D. Resolvin D1 and resolvin E1 promote the resolution of allergic airway inflammation via shared and distinct molecular counter-regulatory pathways.Front Immunol. 2012; 3: 390Crossref PubMed Scopus (45) Google Scholar, 4Uddin M. Levy B.D. Resolvins: natural agonists for resolution of pulmonary inflammation.Prog Lipid Res. 2011; 50: 75-88Crossref PubMed Scopus (80) Google Scholar The formation of these proresolving fatty acids requires the enzymatic activity of 5- and 15-LO, typically from 2 different cell types.4Uddin M. Levy B.D. Resolvins: natural agonists for resolution of pulmonary inflammation.Prog Lipid Res. 2011; 50: 75-88Crossref PubMed Scopus (80) Google Scholar A third category of lipid mediators are the anti-inflammatory electrophilic fatty acids. This group is derived from both n-6 and n-3 fatty acids and include metabolites that contain an α, β-unsaturated carbonyl, epoxide, or the addition of a nitro group on an alkene.5Schopfer F. Cipollina C. Freeman B.A. Formation and signaling actions of electrophilic lipids.Chem Rev. 2011; 111: 5997-6021Crossref PubMed Scopus (232) Google Scholar A plethora of recent studies have shown that they have pleiotropic signaling actions that mediate inflammation by upregulating anti-inflammatory pathways and downregulating proinflammatory signaling. Lastly, the implications of fatty acid dietary intake on asthma will be discussed. PGs and CysLTs are metabolites of AA. AA is cleaved from the sn-2 position of phospholipids by phospholipase A2. In the case of PGs, AA can be a substrate for either of the COX isoforms COX-1, which is constitutively expressed, or COX-2, which is upregulated in inflammation and primarily responsible for PG formation in asthmatic patients. AA is converted to PGG2 in one active site and reduced by the endoperoxide active site to PGH2. Specific synthase enzymes use PGH2 as a substrate, and the resulting products are thromboxane A2, PGI2, PGF2α, PGD2, and PGE2. PGE2 is the most abundant PG in the human body and a major metabolite in the lower respiratory tract.6Sastre B. del Pozo V. Role of PGE2 in asthma and nonasthmatic eosinophilic bronchitis.Mediators Inflamm. 2012; 2012: 645383Crossref PubMed Scopus (48) Google Scholar, 7Velazquez J.R. Teran L.M. Aspirin-intolerant asthma: a comprehensive review of biomarkers and pathophysiology.Clin Rev Allergy Immunol. 2013; 45: 75-86Crossref PubMed Scopus (12) Google Scholar PGE2 has been labeled as proinflammatory because of its multiplicity of effects on the immune system, but in the respiratory system PGE2 is unique in that it has beneficial effects. Cell types that contribute to its production include airway epithelium and smooth muscle, fibroblasts, endothelial cells, and alveolar macrophages.8Fajt M.L. Gelhaus S.L. Freeman B. Uvalle C.E. Trudeau J.B. Holguin F. et al.Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation.J Allergy Clin Immunol. 2013; 131: 1504-1512Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar PGE2 protects against bronchoconstriction, increases relaxation of airway smooth muscle, and has been shown to inhibit the release of mast cell mediators and the recruitment of inflammatory cells.6Sastre B. del Pozo V. Role of PGE2 in asthma and nonasthmatic eosinophilic bronchitis.Mediators Inflamm. 2012; 2012: 645383Crossref PubMed Scopus (48) Google Scholar Many, if not all, of these effects are mediated through one of 4 PGE2 prostanoid G protein–coupled receptors (GPCRs; ie, EP1-EP4).7Velazquez J.R. Teran L.M. Aspirin-intolerant asthma: a comprehensive review of biomarkers and pathophysiology.Clin Rev Allergy Immunol. 2013; 45: 75-86Crossref PubMed Scopus (12) Google Scholar Although PGE2 has been exemplified as an anti-inflammatory PG, PGD2 has been shown to be proinflammatory, despite the fact that they are isomers in which the hydroxyl group and keto group are on opposite sides of the prostanoid ring. Active mast cells generate CysLTs and PGD2. PGD2 is mainly produced from mast cells that contain a hematopoietic PGD2 synthase, and it has been shown that there is a positive correlation of PGD2 concentration to asthma severity in bronchoalveolar lavage fluid.8Fajt M.L. Gelhaus S.L. Freeman B. Uvalle C.E. Trudeau J.B. Holguin F. et al.Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation.J Allergy Clin Immunol. 2013; 131: 1504-1512Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar PGD2 acts through the thromboxane GPCR, the PGD2 receptor 1 (DP1), and the chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes (CRTH2/DP2).8Fajt M.L. Gelhaus S.L. Freeman B. Uvalle C.E. Trudeau J.B. Holguin F. et al.Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation.J Allergy Clin Immunol. 2013; 131: 1504-1512Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar The thromboxane GPCR promotes smooth muscle constriction that likely contributes to bronchoconstriction in asthmatic patients. CRTH2 activation on TH2 lymphocytes, eosinophils, and basophils results in enhanced chemotaxis and activation. CRTH2 receptor binding also induces cytokine production that might play a role in IgE activation by mast cells.8Fajt M.L. Gelhaus S.L. Freeman B. Uvalle C.E. Trudeau J.B. Holguin F. et al.Prostaglandin D(2) pathway upregulation: relation to asthma severity, control, and TH2 inflammation.J Allergy Clin Immunol. 2013; 131: 1504-1512Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar CysLTs are also key mediators of asthma. LTs are derived from AA and synthesized through the 5-LO pathway in conjunction with 5-LO activating protein to catalyze the oxidation of AA to LTA4. The epoxide ring of LTA4 is opened by LTA4 hydrolase to form LTB4 or it is conjugated to glutathione by LTC4 synthase to form LTC4. LTC4 is transported out of the cell by multidrug resistance–associated protein 1. LTC4 is then subjected to extracellular metabolism to form LTD4 (loss of glutamine) and LTE4 (loss of glycine).1Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (2966) Google Scholar These 3 LTs, LTC4, LTD4, and LTE4, comprise the CysLTs. Eosinophils and mast cells are primarily responsible for the synthesis of CysLTs in the context of asthma.1Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (2966) Google Scholar, 2Wenzel S.E. Arachidonic acid metabolites: mediators of inflammation in asthma.Pharmacotherapy. 1997; 17: 3S-12SPubMed Google Scholar Bronchoconstriction, the initiation of proinflammatory cytokine production, and airway remodeling have all been attributed to CysLTs. Additionally, CysLTs have been implicated in the trafficking and degranulation of eosinophils in the lungs, increased microvascular permeability leading to pulmonary edema, and increased mucus secretion.1Funk C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology.Science. 2001; 294: 1871-1875Crossref PubMed Scopus (2966) Google Scholar, 9Misso N.L. Thompson P.J. Prostaglandins and leukotrienes: mediators of inflammation and asthma. Science Publishers, Enfield (NH)2012Google Scholar Unfortunately, only 50% of asthmatic patients show clinical responses to CysLT receptor agonists.9Misso N.L. Thompson P.J. Prostaglandins and leukotrienes: mediators of inflammation and asthma. Science Publishers, Enfield (NH)2012Google Scholar A class of inflammation-resolving fatty acids derived from AA, EPA, and DHA exist that are dihydroxy or trihydroxy in nature. The AA-derived lipoxins and the EPA- and DHA-derived resolvins, protectins, and maresins are produced by dual-enzyme reactions during acute inflammation and are proposed to mediate resolution.10Serhan C.N. Petasis N.A. Resolvins and protectins in inflammation resolution.Chem Rev. 2011; 111: 5922-5943Crossref PubMed Scopus (681) Google Scholar These mediators block neutrophil recruitment, promote infiltration and activation of monocytes, and induce phagocytosis and lymphatic clearance of apoptotic neutrophils by activated macrophages.10Serhan C.N. Petasis N.A. Resolvins and protectins in inflammation resolution.Chem Rev. 2011; 111: 5922-5943Crossref PubMed Scopus (681) Google Scholar These polyhydroxylated species require transcellular biosynthesis, the sequential actions of LOs from neighboring cells (ie, 5-LO/12-LO or 15-LO/5-LO), or they can be formed by a combination of COX-2 and cytochrome P450 or LO.10Serhan C.N. Petasis N.A. Resolvins and protectins in inflammation resolution.Chem Rev. 2011; 111: 5922-5943Crossref PubMed Scopus (681) Google Scholar, 11Serhan C.N. Fredman G. Yang R. Karamnov S. Belayev L.S. Bazan N.G. et al.Novel proresolving aspirin-triggered DHA pathway.Chem Biol. 2011; 18: 976-987Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar The EPA-derived resolvin E1 was shown to dampen airway inflammation and airway hyperresponsiveness (AHR) in a mouse model of asthma.12Aoki H. Hisada T. Ishizuka T. Utsugi M. Kawata T. Shimizu Y. et al.Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma.Biochem Biophys Res Commun. 2008; 367: 509-515Crossref PubMed Scopus (138) Google Scholar Mice administered resolvin E1 had lower eosinophil and lymphocyte recruitment, lower IL-13 and OVA-specific IgE levels, and a lower response to methacholine challenge compared with controls.12Aoki H. Hisada T. Ishizuka T. Utsugi M. Kawata T. Shimizu Y. et al.Resolvin E1 dampens airway inflammation and hyperresponsiveness in a murine model of asthma.Biochem Biophys Res Commun. 2008; 367: 509-515Crossref PubMed Scopus (138) Google Scholar A review by Uddin and Levy4Uddin M. Levy B.D. Resolvins: natural agonists for resolution of pulmonary inflammation.Prog Lipid Res. 2011; 50: 75-88Crossref PubMed Scopus (80) Google Scholar in 2011 summarizes the proresolving role of resolvins in pulmonary inflammation. In a study comparing patients with aspirin-intolerant asthma (AIA) with those with aspirin-tolerant asthma, Sanak et al13Sanak M. Levy B.D. Clish C.B. Chiang N. Gronert K. Mastalerz L. et al.Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics.Eur Respir J. 2000; 16: 44-49Crossref PubMed Scopus (171) Google Scholar reported a reduced generation of lipoxin A4 (LXA4) and aspirin-triggered LXA4 in patients with AIA.13Sanak M. Levy B.D. Clish C.B. Chiang N. Gronert K. Mastalerz L. et al.Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics.Eur Respir J. 2000; 16: 44-49Crossref PubMed Scopus (171) Google Scholar However, Celik et al14Celik G.E. Erkekol F.O. Misirligil Z. Melli M. Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity.Clin Exp Allergy. 2007; 37: 1494-1501PubMed Google Scholar found similar levels of LXA4 in both patients with AIA and those with aspirin-tolerant asthma. This difference might be attributed to a misclassification of asthmatic patients because LXA4 levels are consistently lower in patients with severe asthma, regardless of aspirin tolerance.7Velazquez J.R. Teran L.M. Aspirin-intolerant asthma: a comprehensive review of biomarkers and pathophysiology.Clin Rev Allergy Immunol. 2013; 45: 75-86Crossref PubMed Scopus (12) Google Scholar The actions of these proresolving fatty acids are mediated by their binding to specific GPCRs, including CMKLR1, BLT1, ALX/FPR2, and GPR32.4Uddin M. Levy B.D. Resolvins: natural agonists for resolution of pulmonary inflammation.Prog Lipid Res. 2011; 50: 75-88Crossref PubMed Scopus (80) Google Scholar Additionally, these proresolving species have also been shown to trigger the expression of anti-inflammatory mediators, such as TGF-β and IL-10.4Uddin M. Levy B.D. Resolvins: natural agonists for resolution of pulmonary inflammation.Prog Lipid Res. 2011; 50: 75-88Crossref PubMed Scopus (80) Google Scholar Fat-1 mice15Bilal S. Haworth O. Wu L. Weylandt K.H. Levy B.D. Kang J.X. Fat-1 transgenic mice with elevated omega-3 fatty acids are protected from allergic airway responses.Biochim Biophys Acta. 2011; 1812: 1164-1169Crossref PubMed Scopus (82) Google Scholar express a Caenorhabiditis elegans desaturase that converts n-6 to n-3 fatty acids, thus increasing endogenous anti-inflammatory and proresolving n-3 metabolites. These mice additionally showed a decrease in levels of AA-derived eicosanoids, decreased allergic airway inflammation, and decreased response to methacholine challenge compared with those seen in control mice that were OVA challenged.15Bilal S. Haworth O. Wu L. Weylandt K.H. Levy B.D. Kang J.X. Fat-1 transgenic mice with elevated omega-3 fatty acids are protected from allergic airway responses.Biochim Biophys Acta. 2011; 1812: 1164-1169Crossref PubMed Scopus (82) Google Scholar Polyunsaturated fatty acid (PUFA) oxidation to an α, β-unsaturated ketone or epoxide and the addition of nitrogen dioxide (•NO2) to an alkene result in the formation of electrophilic fatty acid species. Many of these electrophilic fatty acids, such as 17-oxo-DHA, 15deoxyΔ12,14-PGJ2, and nitro-oleic acid (NO2-OA), have been structurally characterized and described as downstream metabolites of n-3 and n-6 PUFAs, but not all have been defined with regard to their biological function, despite their abundance.5Schopfer F. Cipollina C. Freeman B.A. Formation and signaling actions of electrophilic lipids.Chem Rev. 2011; 111: 5997-6021Crossref PubMed Scopus (232) Google Scholar, 16Groeger A.L. Cipollina C. Cole M.P. Woodcock S.R. Bonacci G. Rudolph T.K. et al.Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids.Nat Chem Biol. 2010; 6: 433-441Crossref PubMed Scopus (224) Google Scholar Electrophilic fatty acids function through the posttranslational modification of proteins and transcription factors. Multiple classes of electrophilic signaling molecules are expected to have unique patterns of downstream signaling. Electrophilic fatty acids will adduct susceptible, nucleophilic amino acid residues, such as cysteine and histidine. This adduction induces alterations in protein structure, function, and subcellular distribution.17Batthyany C. Schopfer F.J. Baker P.R. Duran R. Baker L.M. Huang Y. et al.Reversible post-translational modification of proteins by nitrated fatty acids in vivo.J Biol Chem. 2006; 281: 20450-20463Crossref PubMed Scopus (231) Google Scholar The targets for electrophilic fatty acid modification are thus diverse, yielding pleiotropic and sometimes reversible effects on an array of key signaling pathways. The oxo-DHA and oxo-EPA species inhibit proinflammatory cytokine and •NO production and activate Nrf2-dependent gene expression.16Groeger A.L. Cipollina C. Cole M.P. Woodcock S.R. Bonacci G. Rudolph T.K. et al.Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acids.Nat Chem Biol. 2010; 6: 433-441Crossref PubMed Scopus (224) Google Scholar Although dependent on concentration, target specificity, cell type, metabolism, and reversibility,18Lin D. Saleh S. Liebler D.C. 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Freeman B.A. Formation and signaling actions of electrophilic lipids.Chem Rev. 2011; 111: 5997-6021Crossref PubMed Scopus (232) Google Scholar Importantly, the endogenous production of these molecules is often a result of pro-oxidative and stress conditions, thus providing a rheostat mechanism for resolving the inflammatory environment. A recent article by Reddy et al21Reddy A.T. Lakshmi S.P. Dornadula S. Pinni S. Rampa D.R. Reddy R.C. The nitrated Fatty Acid 10-nitro-oleate attenuates allergic airway disease.J Immunol. 2013; 191: 2053-2063Crossref PubMed Scopus (34) Google Scholar demonstrated that 10-NO2-OA decreased airway inflammation and AHR after methacholine challenge to the same extent as fluticasone in a mouse model using ovalbumin as the challenge. In addition, 10-NO2-OA, but not fluticasone, stimulates neutrophil apoptosis and phagocytosis. This was attributed to an increase in PPARγ activity.21Reddy A.T. Lakshmi S.P. Dornadula S. Pinni S. Rampa D.R. Reddy R.C. The nitrated Fatty Acid 10-nitro-oleate attenuates allergic airway disease.J Immunol. 2013; 191: 2053-2063Crossref PubMed Scopus (34) Google Scholar In vitro studies showed that 10-NO2-OA significantly upregulated CD36 expression by alveolar macrophages. This was in contrast to fluticasone treatment, which abolished CD36 expression.21Reddy A.T. Lakshmi S.P. Dornadula S. Pinni S. Rampa D.R. Reddy R.C. The nitrated Fatty Acid 10-nitro-oleate attenuates allergic airway disease.J Immunol. 2013; 191: 2053-2063Crossref PubMed Scopus (34) Google Scholar It has been hypothesized that variations in asthma prevalence across populations and the increase in asthma burden seen in westernized societies over past decades might be related to a combination of a progressively higher intake of n-6 fatty acids, such as LA, which is found in margarine and vegetable oils, and a lower intake of n-3, which is found in marine oils.22Black P.N. Sharpe S. Dietary fat and asthma: is there a connection?.Eur Respir J. 1997; 10: 6-12Crossref PubMed Scopus (425) Google Scholar This concept is largely supported by epidemiologic studies showing that populations with higher n-6 fatty acid consumption have greater asthma prevalence in contrast to those consuming average higher n-3 fatty acid diets, such as the Eskimos.23Horrobin D.F. Low prevalences of coronary heart disease (CHD), psoriasis, asthma and rheumatoid arthritis in Eskimos: are they caused by high dietary intake of EPA, a genetic variation of essential fatty acid (EFA) metabolism or a combination of both?.Med Hypotheses. 1987; 22: 421-428Abstract Full Text PDF PubMed Scopus (124) Google Scholar Given that n-3 fatty acids produces eicosanoids that are less proinflammatory (PGE3 and LTB5 series) than those derived from n-6 fatty acids (PGD2 and LTB4 series) and because downstream metabolites of n-3 fatty acids have the potential to resolve inflammation, the hypothesis that n-3 fatty acid intake could improve asthma by reducing inflammation seems biologically plausible. However, the lack of consistency across observational studies and clinical trials (Table I)24Broadfield E.C. McKeever T.M. Whitehurst A. Lewis S.A. Lawson N. Britton J. et al.A case-control study of dietary and erythrocyte membrane fatty acids in asthma.Clin Exp Allergy. 2004; 34: 1232-1236Crossref PubMed Scopus (36) Google Scholar, 25McKeever T.M. Lewis S.A. Cassano P.A. Ocke M. Burney P. Britton J. et al.The relation between dietary intake of individual fatty acids, FEV1 and respiratory disease in Dutch adults.Thorax. 2008; 63: 208-214Crossref PubMed Scopus (67) Google Scholar, 26Kitz R. Rose M.A. Schubert R. Beermann C. Kaufmann A. Bohles H.J. et al.Omega-3 polyunsaturated fatty acids and bronchial inflammation in grass pollen allergy after allergen challenge.Respir Med. 2010; 104: 1793-1798Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 27Kompauer I. Demmelmair H. Koletzko B. Bolte G. Linseisen J. Heinrich J. Association of fatty acids in serum phospholipids with lung function and bronchial hyperresponsiveness in adults.Eur J Epidemiol. 2008; 23: 175-190Crossref PubMed Scopus (40) Google Scholar, 28Emmanouil E. 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Kaila M. et al.Maternal intake of fatty acids during pregnancy and allergies in the offspring.Br J Nutr. 2012; 108: 720-732Crossref PubMed Scopus (57) Google Scholar certainly raises the possibility that n-3 fatty acids might not be as universally effective as originally considered. Therefore it is possible that these compounds are only effective in select asthma phenotypes.Table IObservational studies on fatty acid exposure and asthma-related outcomesStudy designStudy populationOutcomesResultsCase-control study, United Kingdom24Broadfield E.C. McKeever T.M. Whitehurst A. Lewis S.A. Lawson N. Britton J. et al.A case-control study of dietary and erythrocyte membrane fatty acids in asthma.Clin Exp Allergy. 2004; 34: 1232-1236Crossref PubMed Scopus (36) Google Scholar89 cases of asthma vs 89 community matched control subjects from local registries (mean age 43 y)Fatty acid intake was determined by using FFQ, and erythrocyte membrane levels were determined by using mass spectrometry and odds of asthma.n-3 fatty acids are not protective against asthma, and n-6 fatty acids are associated with lower risk of asthma.Cross-sectional study, The Netherlands25McKeever T.M. Lewis S.A. Cassano P.A. Ocke M. Burney P. Britton J. et al.The relation between dietary intake of individual fatty acids, FEV1 and respiratory disease in Dutch adults.Thorax. 2008; 63: 208-214Crossref PubMed Scopus (67) Google Scholar13,820 subjects (age 20-59 y)Fatty acid intake was determined by using FFQ. Lung function was determined by using spirometry (FEV1 and FVC). A respiratory symptom questionnaire was used regarding reported wheeze, asthma, and COPD symptoms.n-3 intake is not protective against COPD or asthma. High n-6 intake is associated with FEV1 decrease, notably in smokers.Case-control study, Germany26Kitz R. Rose M.A. Schubert R. Beermann C. Kaufmann A. Bohles H.J. et al.Omega-3 polyunsaturated fatty acids and bronchial inflammation in grass pollen allergy after allergen challenge.Respir Med. 2010; 104: 1793-1798Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar38 asthmatic patients with grass pollen allergy vs 19 age-matched healthy control subjects (age 18-45 y)Lung function was measured by using spirometry, and bronchial hyperresponsiveness was measured using methacholine testing, allergen inhalation challenge, and measurement of exhaled NO. Stratification was according to low (Q25) an
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