Scholarly article on topic 'Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases'

Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases Academic research paper on "Chemical sciences"

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Allergology International
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{Allergy / Asthma / "Omega-3 fatty acid" / Protectin / "Specialized pro-resolving mediator"}

Abstract of research paper on Chemical sciences, author of scientific article — Jun Miyata, Makoto Arita

Abstract Omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are found naturally in fish oil and are commonly thought to be anti-inflammatory nutrients, with protective effects in inflammatory diseases including asthma and allergies. The mechanisms of these effects remain mostly unknown but are of great interest for their potential therapeutic applications. Large numbers of epidemiological and observational studies investigating the effect of fish intake or omega-3 fatty acid supplementation during pregnancy, lactation, infancy, childhood, and adulthood on asthmatic and allergic outcomes have been conducted. They mostly indicate protective effects and suggest a causal relationship between decreased intake of fish oil in modernized diets and an increasing number of individuals with asthma or other allergic diseases. Specialized pro-resolving mediators (SPM: protectins, resolvins, and maresins) are generated from omega-3 fatty acids such as EPA and DHA via several enzymatic reactions. These mediators counter-regulate airway eosinophilic inflammation and promote the resolution of inflammation in vivo. Several reports have indicated that the biosynthesis of SPM is impaired, especially in severe asthma, which suggests that chronic inflammation in the lung might result from a resolution defect. This article focuses on the beneficial aspects of omega-3 fatty acids and offers recent insights into their bioactive metabolites including resolvins and protectins.

Academic research paper on topic "Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases"

Accepted Manuscript

Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases Jun Miyata, MD Makoto Arita, PhD

PII: S1323-8930(14)00010-0

DOI: 10.1016/j.alit.2014.08.003

Reference: ALIT 9

To appear in: Allergology International

Received Date: 1 August 2014 Revised Date: 20 August 2014 Accepted Date: 21 August 2014

Please cite this article as: Miyata J, Arita M, Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases, Allergology International (2014), doi: 10.1016/j.alit.2014.08.003.

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Review Invited

Role of omega-3 fatty acids and their metabolites in asthma and allergic diseases

Jun Miyata, MD1, Makoto Arita, PhD 1,2 From:

laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan

2Graduate School of Medical Life Science, Yokohama City University, Kanagawa, Japan

Address for correspondence and reprints

Jun Miyata

Laboratory for Metabolomics

RIKEN Center for Integrative Medical Sciences

1-7-22 Suehirocho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan

Phone: +81-45-503-7075

FAX: +81-45-503-7054


Disclosure: The authors have no conflict of interest to disclose

Total word count: 2558 words

Abstract word count: 205 words

Conflict of interest: The authors have no conflicts of interest to declare. Received: August 1, 2014


Omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are found naturally in fish oil and are commonly thought to be anti-inflammatory nutrients, with protective effects in inflammatory diseases including asthma and allergies. The mechanisms of these effects remain mostly unknown but are of great interest for their potential therapeutic applications. Large numbers of epidemiological and observational studies investigating the effect of fish intake or omega-3 fatty acid supplementation during pregnancy, lactation, infancy, childhood, and adulthood on asthmatic and allergic outcomes have been conducted. They mostly indicate protective effects and suggest a causal relationship between decreased intake of fish oil in modernized diets and an increasing number of individuals with asthma or other allergic diseases. Specialized pro-resolving mediators (SPM: protectins, resolvins, and maresins) are generated from omega-3 fatty acids such as EPA and DHA via several enzymatic reactions. These mediators counter-regulate airway eosinophilic inflammation and promote the resolution of inflammation in vivo. Several reports have indicated that the biosynthesis of SPM is impaired, especially in severe asthma, which suggests that chronic inflammation in the lung might result from a resolution defect. This article focuses on the beneficial aspects of omega-3 fatty acids and offers recent insights into their bioactive metabolites including resolvins and protectins.

Key words:

asthma, allergy, omega-3 fatty acid, specialized pro-resolving mediator, protectin

Abbreviations used

BALF, bronchial alveolar lavage fluid; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HETE, hydroxy-eicosatetraenoic acid; HEPE, hydroxy-eicosapentaenoic acid; IL, interleukin; LC, liquid chromatography; LOX, lipoxygenase; LT, leukotriene; LX, lipoxin; MS/MS, tandem mass spectrometry; PD1, protectin D1; PG, prostaglandin; Rv, resolvin; SPM, specialized pro-resolving mediator; SPT, skin prick test.


Omega-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are polyunsaturated fatty acids found mainly in fish oil. Epidemiological studies have shown that these compounds play protective roles in cardiovascular diseases such as myocardial or cerebral infarction, hypertension, and hyperlipidemia(1). Also, there is a growing evidence that omega-3 fatty acids have beneficial effects in chronic inflammatory diseases including chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, and inflammatory bowel disease(2, 3). In addition, it is thought that atopic sensitization and allergic outcomes also can be prevented by fish intake during pregnancy, infancy, and childhood(4, 5). Contemporary changes in diet resulting in a lower omega-3:omega-6 fatty acid ratio might contribute to exacerbation and increased morbidity of asthma and allergic diseases.

Prostaglandins and leukotrienes are arachidonic acid-derived lipid mediators converted via cyclooxygenase and lipoxygenase, respectively. Prostaglandin D2 and cysteinyl leukotrienes, produced mainly by mast cells and eosinophils, function as potent bronchoconstrictors and pro-inflammatory molecules in allergic airway inflammation(6, 7). Recent biochemical studies showed that omega-3 fatty acids such as DHA and EPA function as precursors for bioactive molecules called resolvins, protectins, and maresins(8, 9). Currently, leukotriene and prostaglandin receptor antagonists are the newest drugs available for the treatment of asthma, but basic research findings now indicate that pro-resolving lipid mediators are potentially the next therapeutic targets for allergic diseases.

Asthma is a common respiratory disease affecting 300 million people

worldwide(10). Inhaled corticosteroids are an established treatment, but 5-10% of asthma patients are resistant to this therapy, leading to difficulties in managing the disease (11). Leukotriene receptor antagonists are widely used as another first-line therapeutic agent in asthma, suggesting that abnormal lipid metabolism contributes to disease pathophysiology. Recently, several reports have indicated that biosynthesis of anti-inflammatory and pro-resolving lipid mediators, lipoxin A4 (LXA4) or protectin D1 (PD1), are dysregulated in severe asthma(12-21), suggesting that an imbalance between pro- and anti-inflammatory molecules causes the exacerbation of inflammation observed in airways of asthmatic patients.

Epidemiological/clinical studies of omega-3 fatty acids in asthma and allergic diseases

A large epidemiological study in Greenland showed that intake of omega-3 fatty acids was inversely associated with asthma morbidity. Since then, many epidemiological and clinical studies focusing on omega-3 fatty acid intake or supplements have been conducted. For example, the concept underlying these studies is supported by the finding that the DHA content compared with arachidonic acid in nasal tissues from patients with asthma was lower than in healthy subjects(22), which suggests a possible protective role of DHA in allergic diseases. Thus, it has been of great interest for some time whether long-chain omega-3 fatty acids or their natural sources, fish or fish oils, have beneficial effects on asthma or other allergic outcomes.

Many epidemiological studies of maternal fish intake during pregnancy have shown beneficial effects on allergic or atopic outcomes in infants or children of those pregnancies(23-27). In addition, the majority of reports investigating fish intake during infancy or childhood have suggested a protective role in allergic outcomes(28-36). These allergic or atopic outcomes included incidence of atopic diseases or symptoms (asthma, wheezing, eczema, and hay fever), food sensitization, and prevalence of positive skin prick test (SPT). One study of fish intake during lactation demonstrated that higher levels of EPA in breast milk correlated with a lower risk of atopic dermatitis(37). On the other hand, observational studies in adults have been inconsistent in showing benefits in asthma of fish or fish oil intake(38-45). However, several reports indicated that omega-3 fatty acid intake lower asthma incidence, prevalence of asthma-related symptoms, or exhaled nitric oxide (NO) levels and improve lung functions in adults(38, 40-43). An epidemiological survey of young adult

Americans revealed that high intake of omega-3 fatty acids, especially DHA compared with EPA, prevented asthma onset(43). These findings raise the possibility that omega-3 fatty acids are useful in the prevention of adult-onset asthma. Another study also demonstrated superiority of DHA compared to other fatty acids in terms of improved lung function(42). A relationship between low omega-3 fatty acid intake and increased respiratory symptoms (chronic bronchitis, wheeze, and asthma) was shown in another study(40), suggesting beneficial effects of omega-3 fatty acids in the lung.

Clinical trials using fish oil supplementation during pregnancy and lactation revealed that maternal intake of fish oil resulted in higher levels of omega-3 fatty acids in the offspring(46-51), along with anti-inflammatory changes in immunological parameters (cytokine production, lipid mediator release, and cellular populations)(51-57). These studies also suggested that fish oil supplementation reduced the prevalence and severity of atopic dermatitis and food sensitization in the first year of life, and that these beneficial effects might persist until adolescence, with a reduced incidence of eczema, hay fever, and asthma(53, 58, 59). Fish oil supplementation in infants and children increased the concentrations of those fatty acids in plasma(60-64) and blood cells(65) and had modulatory effects on the immune systems of infants(65) and children(61, 66). Clinical intervention with fish oil supplements in infants/children from 6 months old to 5 years old showed that there was a decreased prevalence of wheeze and lower bronchodilator use at 18 months of age(63, 67), and reduced allergic sensitization and prevalence of cough at 3 years of age, but without effects on asthma prevalence (64). Two studies examined whether fish oil supplements have beneficial effects on asthmatic symptoms and lung function in patients with asthma in children(61, 68), but in only one study did intervention

significantly reduce asthma severity and improve lung functions(68). The data obtained from clinical trials of fish oil and omega-3 fatty acid supplements in adult asthma are inconsistent. However, several studies demonstrated protective effects of omega-3 fatty acid supplementation in adult asthmatic patients(69-72). Mickleborough, et al., showed that intake of omega-3 fatty acid supplements reduced bronchoconstriction after exercise accompanied by lower production of leukotrienes from polymorphonuclear cells in athletes(7l) and adult patients with asthma(70). Two other reports demonstrated the beneficial and suppressive effects of omega-3-rich supplementation on exhaled NO levels before and after allergen challenge, serum eosinophil counts, eosinophilic cationic protein levels, and in vitro cysteinyl leukotriene release(72), or daytime wheeze, exhaled H2O2 levels, and morning PEF., respectively(69). Various factors, e.g., types of oils, doses, duration, and quality or purity of fish oil or omega-3 fatty acid supplements ^were inconsistent among clinical studies. Characteristics of the subjects in these studies were also different (age, smoking history, country of origin, medication, etc.). There is clearly much room for improvement in study design and protocols to obtain more easily interpretable information.

Omega -3 fatty acids or their metabolites in murine asthma models

To investigate potential beneficial effects of omega-3 fatty acids in asthma, it is of interest to determine whether administration or elevated levels of omega-3 fatty acids can suppress eosinophilic inflammation in vivo. Several reports have indicated that omega-3 fatty acids function as protective molecules in murine models of asthma(73-76), although those regulatory functions were not observed in other studies(77, 78). DHA inhalation during the allergen challenge phase in mice

suppressed airway eosinophilic inflammation, and this was accompanied by reduced numbers of inflammatory cells in bronchoalveolar lavage fluid (BALF) and decreased airway hyperresponsiveness, and mucus production(76). Morin, et al., developed a new monoglyceride DHA derivative (CRBM-0244)(74) and EPA derivative (EPA-MAG)(75) and showed their preventive effects on airway eosinophilic inflammation, airway hyperresponsiveness and inflammatory cytokine production in OVA-induced asthmatic responses.

Fat-1 is a C. elegans enzyme that converts omega-6 fatty acids into omega-3 fatty acids. Fat-1 transgenic mice (Fat-1 mice) have been established and used as an experimental model to determine if higher ratios of omega-3 fatty acids to omega-6 fatty acids can contribute to anti-inflammatory responses in various conditions. In experiments using these mice, substantial amounts of omega-3 fatty acids are detected at steady state baseline in the lung. In a murine model of asthma using OVA, the number of inflammatory cells in BALF, mucus production, airway hyperresponsiveness, and Th2 cytokine concentrations (IL-5, IL-13) were decreased in the fat-1 transgenic mice. Lipidomic analysis demonstrated that the levels of pro-resolving lipid mediators, PD1 and resolvin E1 (RvE1), which are synthesized in lung, were significantly increased in inflamed lungs of fat-1 transgenic mice(73).

Pro-resolving lipid mediators (Protectins • Resolvins • Maresins) Biosynthesis and cell sources of protectins and resolvins

Lipidomic analysis of murine inflammatory exudates or activated cell supernatant identified specific pro-resolving lipid mediators, including protectins, resolvins, and maresins, synthesized from omega-3 fatty acids during the resolution phase. These molecules are generally termed specialized pro-resolving mediators (SPM)(8, 9, 79). Protectins and Resolvin D-series lipid mediators are produced by 15-lipoxygenase in human and 12/15-lipoxygenase in mouse. These enzymes convert DHA to 17-hydro(peroxy)docosapentaenoic acid (17-HpDHA), a compound that is further metabolized into protectins and resolvin Ds. Resolvin E series are produced via the acetylated cyclooxygenase-2 or cytochrome P450 pathways. These enzymes convert EPA to 18-hydroxyeicosapentaenoic acid (18-HEPE), which is further metabolized into resolvin Es. (Figure 1).

15-lipoxygenase or 12/15-lipoxygenase are expressed in Th2 cytokine-stimulated monocyte or macrophages, retinal epithelial cells, microglial cells, and airway epithelial cells. In addition, we demonstrated that human and murine eosinophils highly expressing 15-lipoxygenase-1 or 12/15-lipoxygenase have the capacity to produce PD1(21, 80). We also identified 12/15-lipoxygenase-dependant anti-inflammatory lipid mediators, resolvin E3 and

12-hydroxy-17,18- epoxyeico satetraenoic acid(81-83).

Cyclooxygenase-2 and cytochrome P450 are expressed in neutrophils, macrophages, epithelial cells, and other structural cells. COX-2 is induced by stimulatory signals in various cells types and can modify inflammatory responses thorough its major metabolites, the prostaglandins. Cell-cell interactions between

cells expressing different enzymes are also necessary for the biosynthesis of these mediators(84).

Receptors and biological functions

The search for receptors specific to the newly discovered lipid mediators -protectins, resolvins, and maresins — is now underway, and some receptors with high affinity for resolvin D1 (RvD1), D3, D5 and RvE1 have been identified. However, the receptor specific for PD1 remains unknown, although its existence on neutrophils, pigment epithelial cells, and neuronal cells has been suggested(85, 86). Two high affinity receptors for RvD1 and LXA4, namely ALX (FPR2, FPRL1) and GPR32, were identified (87). GPR32 is also responsive to RvD3 and RvD5(88, 89). RvE1, an EPA-derived lipid mediator, binds to ChemR23, a receptor for chemerin, and antagonizes BLT1, a receptor for LTB4(90-92). These mediators possess pro-resolving functions as inhibitors of neutrophil accumulation into inflammatory sites and promoters of apoptotic cell clearance by macrophages(93). Many types of inflammatory cells, including eosinophil, mast cells, T cells, and dendritic cells, are also directly regulated by these mediators.

Pharmacological effects in a murine models of asthma (Table 1)

(A) Protectin D1 (PD1)

In a murine model of asthma using ovoalbumin (OVA), intravenous administration of PD1 decreased the number of inflammatory cells in BALF and inhibited airway hyperresponsiveness and mucus production, suggesting protective effects on asthmatic responses in vivo without changes of IL-5 concentration in

BALF(94). TLR7 is necessary for the recognition of single stranded RNA of respiratory viruses. TLR7 agonists had preventive effects on allergic airway inflammation in vivo in mice(95-97) and functioned as bronchodilators in humans, indicating that they are potential therapeutic targets in asthma. Interestingly, TLR7 signaling promotes the resolution of airway eosinophilic inflammation through upregulation of 12/15-lipoxygenase metabolism, and its metabolites such as PD1 and RvD1 also showed suppressive effects(98).

(B) Resolvin D1 (RvDl)

Intravenous administration of RvD1 inhibited airway eosinophil accumulation and mucus production with decreased IL-5 production in a murine model of asthma. In vitro, RvD1 promoted phagocytosis by alveolar macrophages, suggesting that RvD1 enhances the clearance of apoptotic inflammatory cells in the airway. Administration of RvD1 during the resolution phase also dampened eosinophilic inflammation(99, 100). As mentioned in the PD1 section, RvD1 promoted the resolution of airway eosinophilic inflammation and its biosynthesis was induced in part thorough the TLR7 cascade(98).

(C) Resolvin E1 (RvE 1)

Various reports have demonstrated the protective effects of RvE 1 on airway eosinophilic inflammation in vivo(l01-104). In an OVA-induced murine asthmatic model, intraperitoneal administration of RvEl during the sensitization phase, challenge phase, or both inhibited the production of OVA-specific IgE, inflammatory cell accumulation in the airways, airway hyperresponsiveness, mucus production, and Th2 cytokine (IL-5, IL-13) production(l01, 102). In addition, intravenous administration of

RvE1 during the resolution phase also dampened inflammatory cell accumulation in the airways, airway hyperresponsiveness, and mucus production. These effects were mediated by the inhibition of Th17 cytokines (IL-17A • IL-23 • IL-6) and the increased production of IFN-g with no differences in Th2 cytokines (IL-5 • IL-13) between vehicle and RvE1 treated groups(104). In this setting, RvE1 directly modulated cytokine production by dendritic cells and activated natural killer (NK) cells(103), the main producers of IFN-g and active inducers of eosinophil apoptosis(105). RvE1 binds to ChemR23, also known as the chemerin receptor. Recently, a new membrane-anchored chemerin receptor agonist was discovered and pharmacological assessment using a murine model of allergic airway inflammation revealed its immunomodulatory functions(106).

Biosynthesis in human asthma (Table2)

(A) Protectin D1(PD1)

The presence of PD1 in the airways of normal human subjects has been documented in condensates of exhaled breath, with a decrease in PD1 levels below the detection limit in exhaled breath condensates of asthmatic patients during exacerbation of the disease(94). We found decreased productions of PD1 and 15-HETE, a 15-lipoxygenase metabolite of arachidonic acid, by stimulated peripheral blood eosinophils from patients with severe asthma, suggesting an impairment in 15-lipoxygenase activity in severe asthma.(21). In contrast, the similar levels of 5-HETE, a 5-lipoxygenase product of arachidonic acid, were observed in patients with severe asthma and healthy subjects, indicating a selectively dysregulated enzymatic activity of 15-lipoxygenase(21) (Figure 2).

Several reports showed decreased biosynthesis or levels of LXA4, a potent anti-inflammatory lipid mediator with suppressive effects on allergic airway inflammation in vivo(107, 108), in BALF (12), exhaled breath condensate(14, 15), whole blood(16-18), and sputum(19, 20) of severe asthmatics. Bhavsar, et al., demonstrated that the alveolar macrophage was one of the specific cell types with impaired LXA4 biosynthetic capacity (13). Similar defects in LXA4 synthesis were observed in aspirin-exacerbated respiratory disease (AERD)(109, 110), asthma exacerbation(111), and exercise-induced bronchoconstriction in asthma(112). Those observations are concordant with our observation of selective dysregulation of PD1 synthesis in human eosinophils, and we propose that impaired fatty acid metabolism may contribute to the pathogenesis of severe asthma. In addition, these observations suggest that dysregulation of a negative feedback system via these pro-resolving molecules might be the underlying pathophysiology in severe asthma. Omega-3 fatty acid supplements might not provide sufficient anti-inflammatory activity because of impaired enzymatic activities in asthma patients. The administration of PD1 or LXA4, or of a molecule that can enhance their synthetic activities, might offer a promising therapeutic strategy for severe asthma.


Epidemiological and observational studies strongly supported the efficacy of omega-3 fatty acids in the prevention or amelioration of asthma and allergic diseases. Molecular mechanisms have been revealed in part by the identification of fatty acid bioactive metabolites. Downstream metabolites generated via lipoxygenase and cyclooxygenase, the specialized pro-resolving mediators (SPM), possess anti-inflammatory properties, offering a more precise understanding of these benefits in inflammatory responses.

Lipidomic analyses revealed dysregulated fatty acid metabolism in patients with allergic diseases, especially severe asthma. The mechanism of dysregulation in the 15-lipoxygenase pathway and its relationship to asthma phenotype (atopy, gender, age, inflammatory cell type, etc.), medication (corticosteroid, leukotriene receptor antagonist, anti-IgE antibody, etc.), or cytokines/chemokines remain to be determined. Further studies of omega-3 fatty acid metabolism and SPM functions might provide therapeutic targets for the prevention and treatment of asthma and other allergic diseases.

1. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet. 2010 Aug 14;376(9740):540-50.

2. Calder PC. Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013 Mar;75(3): 645-62.

3. Yates CM, Calder PC, Ed Rainger G. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol Ther. 2014 Mar;141(3):272-82.

4. Kremmyda LS, Vlachava M, Noakes PS, Diaper ND, Miles EA, Calder PC. Atopy risk in infants and children in relation to early exposure to fish, oily fish, or long-chain omega-3 fatty acids: a systematic review. Clin Rev Allergy Immunol. 2011 Aug;41(1):36-66.

5. Miles EA, Calder PC. Omega-6 and omega-3 polyunsaturated fatty acids and allergic diseases in infancy and childhood. Curr Pharm Des. 2014;20(6):946-53.

6. Laidlaw TM, Boyce JA. Cysteinyl leukotriene receptors, old and new; implications for asthma. Clin Exp Allergy. 2012 Sep;42(9):1313-20.

7. Wenzel SE. Arachidonic acid metabolites: mediators of inflammation in asthma. Pharmacotherapy. 1997 Jan-Feb;17(1 Pt 2):3S-12.

8. Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008 May;8(5):349-61.

9. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005 Dec;6(12):1191-7.

10. Braman SS. The global burden of asthma. Chest. 2006 Jul;130(1 Suppl):4S-12S.

11. Bell MC, Busse WW. Severe asthma: an expanding and mounting clinical challenge. J Allergy Clin Immunol Pract. 2013 Mar;1(2):110-21; quiz 22.

12. Planaguma A, Kazani S, Marigowda G, Haworth O, Mariani TJ, Israel E, et al. Airway lipoxin A4 generation and lipoxin A4 receptor expression are decreased in severe asthma. Am J Respir Crit Care Med. 2008 Sep 15;178(6):574-82.

13. Bhavsar PK, Levy BD, Hew MJ, Pfeffer MA, Kazani S, Israel E, et al. Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma. Respir Res. 2010;11:71.

14. Kazani S, Planaguma A, Ono E, Bonini M, Zahid M, Marigowda G, et al. Exhaled breath condensate eicosanoid levels associate with asthma and its severity. J Allergy Clin Immunol. 2013 Sep;132(3):547-53.

15. Fritscher LG, Post M, Rodrigues MT, Silverman F, Balter M, Chapman KR, et

al. Profile of eicosanoids in breath condensate in asthma and COPD. J Breath Res. 2012 Jun;6(2):026001.

16. Levy BD, Bonnans C, Silverman ES, Palmer LJ, Marigowda G, Israel E. Diminished lipoxin biosynthesis in severe asthma. Am J Respir Crit Care Med. 2005 Oct 1;172(7):824-30.

17. Celik GE, Erkekol FO, Misirligil Z, Melli M. Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity. Clin Exp Allergy. 2007 Oct;37(10):1494-501.

18. Wu SH, Yin PL, Zhang YM, Tao HX. Reversed changes of lipoxin A4 and leukotrienes in children with asthma in different severity degree. Pediatr Pulmonol. 2010 Apr;45(4):333-40.

19. Bonnans C, Vachier I, Chavis C, Godard P, Bousquet J, Chanez P. Lipoxins are potential endogenous antiinflammatory mediators in asthma. Am J Respir Crit Care Med. 2002 Jun 1;165(11):1531-5.

20. Vachier I, Bonnans C, Chavis C, Farce M, Godard P, Bousquet J, et al. Severe asthma is associated with a loss of LX4, an endogenous anti-inflammatory compound. J Allergy Clin Immunol. 2005 Jan;115(1):55-60.

21. Miyata J, Fukunaga K, Iwamoto R, Isobe Y, Niimi K, Takamiya R, et al. Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma. J Allergy Clin Immunol. 2013 Feb;131(2):353-60 e1-2.

22. Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med. 2004 Feb 5;350(6):560-9.

23. Calvani M, Alessandri C, Sopo SM, Panetta V, Pingitore G, Tripodi S, et al. Consumption of fish, butter and margarine during pregnancy and development of allergic sensitizations in the offspring: role of maternal atopy. Pediatr Allergy Immunol. 2006 Mar;17(2):94-102.

24. Romieu I, Torrent M, Garcia-Esteban R, Ferrer C, Ribas-Fito N, Anto JM, et al. Maternal fish intake during pregnancy and atopy and asthma in infancy. Clin Exp Allergy. 2007 Apr;37(4):518-25.

25. Salam MT, Li YF, Langholz B, Gilliland FD. Maternal fish consumption during pregnancy and risk of early childhood asthma. J Asthma. 2005 Jul-Aug;42(6):513-8.

26. Sausenthaler S, Koletzko S, Schaaf B, Lehmann I, Borte M, Herbarth O, et al. Maternal diet during pregnancy in relation to eczema and allergic sensitization in the offspring at 2 y of age. Am J Clin Nutr. 2007 Feb;85(2):530-7.

27. Willers SM, Devereux G, Craig LC, McNeill G, Wijga AH, Abou El-Magd W,

et al. Maternal food consumption during pregnancy and asthma, respiratory and atopic symptoms in 5-year-old children. Thorax. 2007 Sep;62(9):773-9.

28. Andreasyan K, Ponsonby AL, Dwyer T, Kemp A, Dear K, Cochrane J, et al. A differing pattern of association between dietary fish and allergen-specific subgroups of atopy. Allergy. 2005 May;60(5):671-7.

29. Antova T, Pattenden S, Nikiforov B, Leonardi GS, Boeva B, Fletcher T, et al. Nutrition and respiratory health in children in six Central and Eastern European countries. Thorax. 2003 Mar;58(3):231-6.

30. Chatzi L, Torrent M, Romieu I, Garcia-Esteban R, Ferrer C, Vioque J, et al. Diet, wheeze, and atopy in school children in Menorca, Spain. Pediatr Allergy Immunol. 2007 Sep;18(6):480-5.

31. Dunder T, Kuikka L, Turtinen J, Rasanen L, Uhari M. Diet, serum fatty acids, and atopic diseases in childhood. Allergy. 2001 May;56(5):425-8.

32. Hodge L, Salome CM, Peat JK, Haby MM, Xuan W, Woolcock AJ. Consumption of oily fish and childhood asthma risk. Med J Aust. 1996 Feb 5;164(3):137-40.

33. Huang SL, Lin KC, Pan WH. Dietary factors associated with physician-diagnosed asthma and allergic rhinitis in teenagers: analyses of the first Nutrition and Health Survey in Taiwan. Clin Exp Allergy. 2001 Feb;31(2):259-64.

34. Kim JL, Elfman L, Mi Y, Johansson M, Smedje G, Norback D. Current asthma and respiratory symptoms among pupils in relation to dietary factors and allergens in the school environment. Indoor Air. 2005 Jun;15(3):170-82.

35. Kull I, Bergstrom A, Lilja G, Pershagen G, Wickman M. Fish consumption during the first year of life and development of allergic diseases during childhood. Allergy. 2006 Aug;61 (8):1009-15.

36. Nafstad P, Nystad W, Magnus P, Jaakkola JJ. Asthma and allergic rhinitis at 4 years of age in relation to fish consumption in infancy. J Asthma. 2003 Jun;40(4):343-8.

37. Hoppu U, Rinne M, Lampi AM, Isolauri E. Breast milk fatty acid composition is associated with development of atopic dermatitis in the infant. J Pediatr Gastroenterol Nutr. 2005 Sep;41(3):335-8.

38. Barros R, Moreira A, Fonseca J, Delgado L, Castel-Branco MG, Haahtela T, et al. Dietary intake of alpha-linolenic acid and low ratio of n-6:n-3 PUFA are associated with decreased exhaled NO and improved asthma control. Br J Nutr. 2011 Aug;106(3):441-50.

39. Broadfield EC, McKeever TM, Whitehurst A, Lewis SA, Lawson N, Britton J, et al. A case-control study of dietary and erythrocyte membrane fatty acids in asthma.

Clin Exp Allergy. 2004 Aug;34(8):1232-6.

40. Burns JS, Dockery DW, Neas LM, Schwartz J, Coull BA, Raizenne M, et al. Low dietary nutrient intakes and respiratory health in adolescents. Chest. 2007 Jul;132(1):238-45.

41. Kitz R, Rose MA, Schubert R, Beermann C, Kaufmann A, Bohles HJ, et al. Omega-3 polyunsaturated fatty acids and bronchial inflammation in grass pollen allergy after allergen challenge. Respir Med. 2010 Dec;104(12): 1793-8.

42. Kompauer 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(3): 175-90.

43. Li J, Xun P, Zamora D, Sood A, Liu K, Daviglus M, et al. Intakes of long-chain omega-3 (n-3) PUFAs and fish in relation to incidence of asthma among American young adults: the CARDIA study. Am J Clin Nutr. 2013 Jan;97(1):173-8.

44. McKeever TM, Lewis SA, Cassano PA, 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 Mar;63(3):208-14.

45. Woods RK, Raven JM, Walters EH, Abramson MJ, Thien FC. Fatty acid levels and risk of asthma in young adults. Thorax. 2004 Feb;59(2): 105-10.

46. Barden AE, Mori TA, Dunstan JA, Taylor AL, Thornton CA, Croft KD, et al. Fish oil supplementation in pregnancy lowers F2-isoprostanes in neonates at high risk of atopy. Free Radic Res. 2004 Mar;38(3):233-9.

47. Dunstan JA, Mitoulas LR, Dixon G, Doherty DA, Hartmann PE, Simmer K, et al. The effects of fish oil supplementation in pregnancy on breast milk fatty acid composition over the course of lactation: a randomized controlled trial. Pediatr Res. 2007 Dec;62(6):689-94.

48. Dunstan JA, Mori TA, Barden A, Beilin LJ, Holt PG, Calder PC, et al. Effects of n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition. Eur J Clin Nutr. 2004 Mar;58(3):429-37.

49. Dunstan JA, Roper J, Mitoulas L, Hartmann PE, Simmer K, Prescott SL. The effect of supplementation with fish oil during pregnancy on breast milk immunoglobulin A, soluble CD14, cytokine levels and fatty acid composition. Clin Exp Allergy. 2004 Aug;34(8):1237-42.

50. Krauss-Etschmann S, Shadid R, Campoy C, Hoster E, Demmelmair H, Jimenez M, et al. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial. Am J Clin Nutr. 2007 May;85(5): 1392-400.

51. Warstedt K, Furuhjelm C, Duchen K, Falth-Magnusson K, Fageras M. The effects of omega-3 fatty acid supplementation in pregnancy on maternal eicosanoid, cytokine, and chemokine secretion. Pediatr Res. 2009 Aug;66(2):212-7.

52. Denburg JA, Hatfield HM, Cyr MM, Hayes L, Holt PG, Sehmi R, et al. Fish oil supplementation in pregnancy modifies neonatal progenitors at birth in infants at risk of atopy. Pediatr Res. 2005 Feb;57(2):276-81.

53. Dunstan JA, Mori TA, Barden A, Beilin LJ, Taylor AL, Holt PG, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003 Dec;112(6):1178-84.

54. Dunstan JA, Mori TA, Barden A, Beilin LJ, Taylor AL, Holt PG, et al. Maternal fish oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy. Clin Exp Allergy. 2003 Apr;33(4):442-8.

55. Krauss-Etschmann S, Hartl D, Rzehak P, Heinrich J, Shadid R, Del Carmen Ramirez-Tortosa M, et al. Decreased cord blood IL-4, IL-13, and CCR4 and increased TGF-beta levels after fish oil supplementation of pregnant women. J Allergy Clin Immunol. 2008 Feb;121(2):464-70 e6.

56. Lauritzen L, Kjaer TM, Fruekilde MB, Michaelsen KF, Frokiaer H. Fish oil supplementation of lactating mothers affects cytokine production in 2 1/2-year-old children. Lipids. 2005 Jul;40(7):669-76.

57. Prescott SL, Barden AE, Mori TA, Dunstan JA. Maternal fish oil supplementation in pregnancy modifies neonatal leukotriene production by cord-blood-derived neutrophils. Clin Sci (Lond). 2007 Nov;113(10):409-16.

58. Furuhjelm C, Warstedt K, Larsson J, Fredriksson M, Bottcher MF, Falth-Magnusson K, et al. Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy. Acta Paediatr. 2009 Sep;98(9):1461-7.

59. Olsen SF, Osterdal ML, Salvig JD, Mortensen LM, Rytter D, Secher NJ, et al. Fish oil intake compared with olive oil intake in late pregnancy and asthma in the offspring: 16 y of registry-based follow-up from a randomized controlled trial. Am J Clin Nutr. 2008 Jul;88(1):167-75.

60. Almqvist C, Garden F, Xuan W, Mihrshahi S, Leeder SR, Oddy W, et al. Omega-3 and omega-6 fatty acid exposure from early life does not affect atopy and asthma at age 5 years. J Allergy Clin Immunol. 2007 Jun;119(6):1438-44.

61. Hodge L, Salome CM, Hughes JM, Liu-Brennan D, Rimmer J, Allman M, et al. Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children. Eur Respir J. 1998 Feb;11(2):361-5.

62. Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol. 2006 Jul;118(1):53-61.

63. Mihrshahi S, Peat JK, Marks GB, Mellis CM, Tovey ER, Webb K, et al. Eighteen-month outcomes of house dust mite avoidance and dietary fatty acid modification in the Childhood Asthma Prevention Study (CAPS). J Allergy Clin Immunol. 2003 Jan;111(1):162-8.

64. Peat JK, Mihrshahi S, Kemp AS, Marks GB, Tovey ER, Webb K, et al. Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study. J Allergy Clin Immunol. 2004 Oct;114(4):807-13.

65. Damsgaard CT, Lauritzen L, Kjaer TM, Holm PM, Fruekilde MB, Michaelsen KF, et al. Fish oil supplementation modulates immune function in healthy infants. J Nutr. 2007 Apr;137(4):1031-6.

66. Vaisman N, Zaruk Y, Shirazi I, Kaysar N, Barak V. The effect of fish oil supplementation on cytokine production in children. Eur Cytokine Netw. 2005 Sep;16(3):194-8.

67. Mihrshahi S, Peat JK, Webb K, Oddy W, Marks GB, Mellis CM. Effect of omega-3 fatty acid concentrations in plasma on symptoms of asthma at 18 months of age. Pediatr Allergy Immunol. 2004 Dec;15(6):517-22.

68. Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K. Dietary supplementation with fish oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma. Eur Respir J. 2000 Nov;16(5):861-5.

69. Emelyanov A, Fedoseev G, Krasnoschekova O, Abulimity A, Trendeleva T, Barnes PJ. Treatment of asthma with lipid extract of New Zealand green-lipped mussel: a randomised clinical trial. Eur Respir J. 2002 Sep;20(3):596-600.

70. Mickleborough TD, Lindley MR, Ionescu AA, Fly AD. Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma. Chest. 2006 Jan;129(1):39-49.

71. Mickleborough TD, Murray RL, Ionescu AA, Lindley MR. Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletes. Am J Respir Crit Care Med. 2003 Nov 15;168(10):1181-9.

72. Schubert R, Kitz R, Beermann C, Rose MA, Lieb A, Sommerer PC, et al. Effect of n-3 polyunsaturated fatty acids in asthma after low-dose allergen challenge. Int Arch Allergy Immunol. 2009;148(4):321-9.

73. Bilal S, Haworth O, Wu L, Weylandt KH, Levy BD, Kang JX. Fat-1 transgenic

mice with elevated omega-3 fatty acids are protected from allergic airway responses. Biochim Biophys Acta. 2011 Sep;1812(9):1164-9.

74. Morin C, Fortin S, Cantin AM, Rousseau E. Docosahexaenoic acid derivative prevents inflammation and hyperreactivity in lung: implication of PKC-Potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kD in asthma. Am J Respir Cell Mol Biol. 2011 Aug;45(2):366-75.

75. Morin C, Fortin S, Cantin AM, Rousseau E. MAG-EPA resolves lung inflammation in an allergic model of asthma. Clin Exp Allergy. 2013 Sep;43(9):1071-82.

76. Yokoyama A, Hamazaki T, Ohshita A, Kohno N, Sakai K, Zhao GD, et al. Effect of aerosolized docosahexaenoic acid in a mouse model of atopic asthma. Int Arch Allergy Immunol. 2000 Dec;123(4):327-32.

77. Schuster GU, Bratt JM, Jiang X, Pedersen TL, Grapov D, Adkins Y, et al. Dietary long-chain omega-3 fatty acids do not diminish eosinophilic pulmonary inflammation in mice. Am J Respir Cell Mol Biol. 2014 Mar;50(3):626-36.

78. Yin H, Liu W, Goleniewska K, Porter NA, Morrow JD, Peebles RS, Jr. Dietary supplementation of omega-3 fatty acid-containing fish oil suppresses F2-isoprostanes but enhances inflammatory cytokine response in a mouse model of ovalbumin-induced allergic lung inflammation. Free Radic Biol Med. 2009 Sep 1;47(5):622-8.

79. Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014 Mar 20;40(3):315-27.

80. Yamada T, Tani Y, Nakanishi H, Taguchi R, Arita M, Arai H. Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice. FASEB J. 2011 Feb;25(2):561-8.

81. Isobe Y, Arita M, Iwamoto R, Urabe D, Todoroki H, Masuda K, et al. Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3. J Biochem. 2013 Apr;153(4):355-60.

82. Isobe Y, Arita M, Matsueda S, Iwamoto R, Fujihara T, Nakanishi H, et al. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. J Biol Chem. 2012 Mar 23;287(13):10525-34.

83. Kubota T, Arita M, Isobe Y, Iwamoto R, Goto T, Yoshioka T, et al. Eicosapentaenoic acid is converted via omega-3 epoxygenation to the anti-inflammatory metabolite 12-hydroxy-17,18-epoxyeicosatetraenoic acid. FASEB J. 2014 Feb;28(2):586-93.

84. Chiang N, Serhan CN, Dahlen SE, Drazen JM, Hay DW, Rovati GE, et al. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol Rev. 2006 Sep;58(3):463-87.

85. Marcheselli VL, Mukheijee PK, Arita M, Hong S, Antony R, Sheets K, et al. Neuroprotectin D1/protectin D1 stereoselective and specific binding with human retinal pigment epithelial cells and neutrophils. Prostaglandins Leukot Essent Fatty Acids. 2010 Jan;82(1):27-34.

86. Park CK, Lu N, Xu ZZ, Liu T, Serhan CN, Ji RR. Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci. 2011 Oct 19;31(42):15072-85.

87. Krishnamoorthy S, Recchiuti A, Chiang N, Yacoubian S, Lee CH, Yang R, et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4): 1660-5.

88. Chiang N, Fredman G, Backhed F, Oh SF, Vickery T, Schmidt BA, et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature.

2012 Apr 26;484(7395):524-8.

89. Dalli J, Winkler JW, Colas RA, Arnardottir H, Cheng CY, Chiang N, et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem Biol.

2013 Feb 21;20(2):188-201.

90. Arita M, Bianchini F, Aliberti J, Sher A, Chiang N, Hong S, et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med. 2005 Mar 7;201(5):713-22.

91. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. J Immunol. 2007 Mar 15;178(6):3912-7.

92. Ohira T, Arita M, Omori K, Recchiuti A, Van Dyke TE, Serhan CN. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J Biol Chem. 2010 Jan 29;285(5):3451-61.

93. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007 Jun 14;447(7146):869-74.

94. Levy BD, Kohli P, Gotlinger K, Haworth O, Hong S, Kazani S, et al. Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness. J Immunol. 2007 Jan 1;178(1):496-502.

95. Camateros P, Tamaoka M, Hassan M, Marino R, Moisan J, Marion D, et al. Chronic asthma-induced airway remodeling is prevented by toll-like receptor-7/8 ligand S28463. Am J Respir Crit Care Med. 2007 Jun 15;175(12):1241-9.

96. Grela F, Aumeunier A, Bardel E, Van LP, Bourgeois E, Vanoirbeek J, et al. The TLR7 agonist R848 alleviates allergic inflammation by targeting invariant NKT cells to produce IFN-gamma. J Immunol. 2011 Jan 1;186(1):284-90.

97. Xirakia C, Koltsida O, Stavropoulos A, Thanassopoulou A, Aidinis V, Sideras P, et al. Toll-like receptor 7-triggered immune response in the lung mediates acute and long-lasting suppression of experimental asthma. Am J Respir Crit Care Med. 2010 Jun 1;181(11):1207-16.

98. Koltsida O, Karamnov S, Pyrillou K, Vickery T, Chairakaki AD, Tamvakopoulos C, et al. Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation. EMBO Mol Med. 2013 May;5(5):762-75.

99. Levy BD. Resolvin D1 and Resolvin E1 Promote the Resolution of Allergic Airway Inflammation via Shared and Distinct Molecular Counter-Regulatory Pathways. Front Immunol. 2012;3:390.

100. Rogerio AP, Haworth O, Croze R, Oh SF, Uddin M, Carlo T, et al. Resolvin D1 and aspirin-triggered resolvin D1 promote resolution of allergic airways responses. J Immunol. 2012 Aug 15;189(4):1983-91.

101. Aoki 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 Mar 7;367(2):509-15.

102. Aoki H, Hisada T, Ishizuka T, Utsugi M, Ono A, Koga Y, et al. Protective effect of resolvin E1 on the development of asthmatic airway inflammation. Biochem Biophys Res Commun. 2010 Sep 10;400(1):128-33.

103. Haworth O, Cernadas M, Levy BD. NK cells are effectors for resolvin E1 in the timely resolution of allergic airway inflammation. J Immunol. 2011 Jun 1;186(11):6129-35.

104. Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation. Nat Immunol. 2008 Aug;9(8):873-9.

105. Barnig C, Cernadas M, Dutile S, Liu X, Perrella MA, Kazani S, et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci Transl Med. 2013 Feb 27;5(174):174ra26.

106. Doyle JR, Krishnaji ST, Zhu G, Xu ZZ, Heller D, Ji RR, et al. Development of a Membrane-anchored Chemerin Receptor Agonist as a Novel Modulator of Allergic Airway Inflammation and Neuropathic Pain. J Biol Chem. 2014 May 9;289(19):13385-96.

107. Levy BD, De Sanctis GT, Devchand PR, Kim E, Ackerman K, Schmidt BA, et al. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4). Nat Med. 2002 Sep;8(9):1018-23.

108. Levy BD, Lukacs NW, Berlin AA, Schmidt B, Guilford WJ, Serhan CN, et al. Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism. FASEB J. 2007 Dec;21(14):3877-84.

109. Sanak M, Levy BD, Clish CB, Chiang N, Gronert K, Mastalerz L, et al. Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. Eur Respir J. 2000 Jul;16(1):44-9.

110. Yamaguchi H, Higashi N, Mita H, Ono E, Komase Y, Nakagawa T, et al. Urinary concentrations of 15-epimer of lipoxin A(4) are lower in patients with aspirin-intolerant compared with aspirin-tolerant asthma. Clin Exp Allergy. 2011 Dec;41(12):1711-8.

111. Hasan RA, O'Brien E, Mancuso P. Lipoxin A(4) and 8-isoprostane in the exhaled breath condensate of children hospitalized for status asthmaticus. Pediatr Crit Care Med. 2012 Mar;13(2):141-5.

112. Tahan F, Saraymen R, Gumus H. The role of lipoxin A4 in exercise-induced bronchoconstriction in asthma. J Asthma. 2008 Mar;45(2):161-4.

Figure legends

Figure 1. Polyunsaturated fatty acid-derived lipid mediators.

Arachidonic acid is a metabolic precursor to eicosanoids (i.e. prostaglandins and leukotrienes) that have distinct roles as pro-inflammatory mediators. In contrast, omega-3 fatty acids are converted to bioactive metabolites such as resolvins and protectins with anti-inflammatory and pro-resolving properties.

Figure 2. Dysregulation of 15-lipoxygenase pathway in eosinophil from patients with severe asthma.

There was a surprisingly marked decrease in the biosynthesis of PD1 by stimulated peripheral blood eosinophils harvested from patients with severe asthma. In contrast, the levels of 5-HETE, a 5-lipoxygenase-dependent metabolite of arachidonic acid, were similar in patients and healthy subjects, suggesting a selective dysregulation of the 15-lipoxygenase pathway.

Table 1. Pharmacological effects of SPM in murine models of asthma

Table2. Impaired biosynthesis of SPM in patients with asthma (severe asthma, asthma exacerbation, AERD, and bronchoconstriction)

SPM Administration Timing Inflammatory cell (BALF) Cytokines, Lipid mediators AHR Mucin Reference

Sensitization Challenge Resolution

PD1 I.V. o o EOS- LYM- IL-5^ IL-13- PGD2- cysLTs- - - 94

RvD1 I.V., I.N. o o EOS- LYM- M®t IL-4^ IL-5- IL-10^ IL-13^ IL-17- IL-23-CCL11^ CCL17^ IFN-y^ LTB4- LXA4^ - - 100

RvE1 I.P. o o EOS- LYM- IL-4- IL-5- IL-13- CCL5- I g E- - - 101, 102

RvE1 I.V. o o EOS- LYM- NKt IL-4^ IL-5^ IL-13^ IL-6- IL-17- IL-23- IL-27- IFN-yt LTB4-cysLTs^ LXA4t - - 103, 104

LXA4 I.V. o EOS- LYM- IL-5- IL-13- PGE2- cysLTs- - ND 107

LXA4 analog I.V. o EOS- LYM- IL-4- IL-5- IL-13- IL-10-CCL5^ cysLTs- - ND 108

Abbreviation: SPM, specific proresolving mediator; I.V., intravenous; I.N., intranasal; EOS, eosinophil; LYM. Lymphocyte; MË, macrophage; NK, natural killer cell; AHR, airway hyperresponsiveness; ND, no data.

SPM Disease Clinical sample Cell type Findings Reference

PD1 Severe asthma WB EOS Decreased PD1 synthesis in eosinophils from severe asthmatics 21

Asthma exacerbation EBC Decreased PD1 concentration during asthma exacerbation 94

LXA4 Severe asthma BALF, EBBs, WB NEU, EOS, MONO, LYM Decreased LXA4 concentration in BALF and ALXR expressions on granulocytes in severe asthma 12

BALF Alveolar ИФ Lower LXA4 generation in alveolar MF from severe asthmatics compaired with non-severe asthmatics 13

EBC The LXA4/LTB4 ratio is decreased in severe asthma 14

EBC Lower LXA4 concentration in severe to moderate asthma 15

than in intermittent asthma and healthy status

WB Lower LXA4 synthesis in severe asthma than in moderate asthma 16

with higher CysLTs synthesis

WB Lower LXA4 generation in severe asthma than in mild asthma 17

WB LEU Decreased 15-LOX expressions in leukocytes and LXA4 18

concentration in severe asthma than in mild to moderate asthma

Sputum Lower LXA4 concentration in severe asthma than in mild asthma with higher IL-8 concentration 19, 20

AERD WB Urine Lower LXA4 and 15-epi LXA4 synthesis in AIA than in ATA Lower 15-epi LXA4 concentration inAIA 109 110

Asthma exacerbation EBC Lower LXA4 concentration in asthma than in status asthmatics 111

Bronchoconstriction WB Lower LXA4 concentration after exercise in mild asthma 112

Abbreviation: AERD, aspirin-exacerbated respiratory disease; BALF, bronchial alveolar lavage fluid; EBBs, endobronchial lung biopsy; WB, whole blood; EBC, exhaled breath conensate; NEU, neutrophil; EOS, eosinophil; MONO, monocyte; LYM, Lymphocyte; MO, macrophage; LEU, leukocytes; CysLTs, cysteinyl leukotrine; LOX, lipoxygenase; ATA, aspirin-tolerant asthma ; AIA, aspirin-intolerant asthma.

Omega-6 fatty acid

Omega-3 fatty acid


Arachidonic acid (AA, 20:4n-6)

Eicosapentaenoic acid (EPA, 20:5n-3)

Docosahexaenoic acid (DHA, 22:6n-3)



Cyclooxygenase (COX) • Lipoxygenase(LOX) • Cytochrome P450(CYP)

Resolvin E series

Protectin Resolvin D series Maresin

Lipoxin A4

Resolvin E3

Maresin 1


Dysregulation in severe asthma




Lipoxin A4

Protectin D1

Protectin D1


HS:Healthy subjects SA: Severe asthmatics

HS SA HS SA _10 10