Bioactive lipids: Accessible indicators toward improved diagnosis and treatment of asthma

Polyunsaturated fatty acids (PUFAs) are lipid mediators that can act at cognate receptors (G protein–coupled receptors) or be converted to a diverse range of bioactive oxylipins, through either nonenzymatic or enzymatic pathways. These pathways include lipoxygenase (LO), COX, and cytochrome P450 enzymes. Metabolomic studies conducted using the serum and bronchoalveolar lavage fluid (BALF) of asthmatic patients have identified PUFAs and oxylipins that contribute to the pathogenesis of asthma.1Reinke S.N. Gallart-Ayala H. Gomez C. Checa A. Fauland A. Naz S. et al.Metabolomics analysis identifies different metabotypes of asthma severity.Eur Respir J. 2017; 491601740Crossref Scopus (102) Google Scholar,2McGeachie M.J. Dahlin A. Qiu W. Croteau-Chonka D.C. Savage J. Wu A.C. et al.The metabolomics of asthma control: a promising link between genetics and disease.Immun Inflamm Dis. 2015; 3: 224-238Crossref PubMed Scopus (60) Google Scholar In particular, the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) generate specialized proresolving mediators that reportedly ameliorate respiratory symptoms in asthmatics subjects3Barnig C. Frossard N. Levy B.D. Towards targeting resolution pathways of airway inflammation in asthma.Pharmacol Ther. 2018; 186: 98-113Crossref PubMed Scopus (51) Google Scholar and likely compete with omega-6 PUFAs for enzymatic metabolism (Fig 1). Indeed, the ratio of these lipids may be relevant to asthma development, as intake of EPA and DHA from fish oil was associated with a reduced risk of asthma development in children carrying a mutation in fatty acid desaturase,4Talaei M. Sdona E. Calder P.C. Jones L.R. Emmett P.M. Granell R. et al.Intake of n-3 polyunsaturated fatty acids in childhood, FADS genotype and incident asthma.Eur Respir J. 2021; 582003633Crossref Scopus (6) Google Scholar an enzyme that generates omega-3 EPA and DHA from α-linolenic acid in addition to omega-6 arachidonic acid (AA) from linoleic acid (LA) (Fig 1). However, a layer of complexity comes from the opposing function of oxylipins derived from omega-6 PUFAs through different enzymatic pathways. For instance, metabolism of AA through the 5-, 15- and 12-LO pathways, produces proinflammatory cysteinyl-leukotrienes, 15-hydroxy-eicosatetraenoic acid, and anti-inflammatory lipoxin A4, respectively. Additionally, in the COX pathway, prostaglandin (PG)E2, PGF2α, and 15-deoxy-PGJ2 may exert proinflammatory and anti-inflammatory functions in the lung. Therefore, a comprehensive analysis of all oxylipins present in patients with asthma will be essential to understanding their contribution to asthma pathobiology and endotypes.5Kelly R.S. Mendez K.M. Huang M. Hobbs B.D. Clish C.B. Gerszten R. et al.Metabo-endotypes of asthma reveal differences in lung function: discovery and validation in two TOPMed cohorts.Am J Respir Crit Care Med. 2022; 205: 288-299Crossref Scopus (3) Google Scholar Ultimately, personalized treatment of asthma would ideally include selectively inhibiting or potentiating the enzymatic pathways leading to these potent lipid mediators.One significant barrier to understanding the role of oxylipins in asthma is the difficulty in measuring them in accessible tissue. In this issue of the Journal of Allergy and Clinical Immunology, Johnson et al6Johnson R.K. Manke J. Campbell M. Armstrong M. Boorgula M.P. Pinheiro G. et al.Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.J Allergy Clin Immunol. 2022; 150: 965-971.e8Abstract Full Text Full Text PDF Scopus (1) Google Scholar analyzed 56 oxylipins obtained from brushing the nasal cavities of 11 female subjects, including healthy subjects who did not have atopic asthma (n = 3), subjects with mild-to-moderate atopic asthma (n = 4), and subjects with severe atopic asthma (n = 4), as classified by the Global Initiative for Asthma guidelines. Although only the levels of 9,10-dihydroxy-octadecenoic acid were significantly different across the groups in this small study, principal component analysis across samples identified a reduction in the levels of omega-3–derived oxylipins and an increase in levels of omega-6–derived–oxylipins in principal component 3 (PC3) that was associated with asthma. Specifically, the omega-6–derived oxylipins found at increased levels in PC3 included 13 hydroxy-octadecadienoic acid (13-HODE), a 15-LO product of LA (Fig 1), and 13-oxooctadecadienoic acid, a product of further LA metabolism. Notably, in a prior study assessing oxylipin levels in subjects with asthma, increases in 13-HODE were detected in the bronchial wash but not in the BALF, as compared with the levels in the controls.7Larsson N. Lundstrom S.L. Pinto R. Rankin G. Karimpour M. Blomberg A. et al.Lipid mediator profiles differ between lung compartments in asthmatic and healthy humans.Eur Respir J. 2014; 43: 453-463Crossref Scopus (19) Google Scholar Furthermore, another study of oxylipins in the BALF of asthmatic subjects and controls reported increases in the levels of 15-hydroxy-eicosatetraenoic acid, 9,10-dihydroxy-octadecenoic acid, and 12,13-dihydroxy-octadecenoic acid, which are AA- and LA-derived metabolites of the 15-LO and cytochrome 450 pathways, respectively.8Lundstrom S.L. Yang J. Kallberg H.J. Thunberg S. Gafvelin G. Haeggstrom J.Z. et al.Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation.PLoS One. 2012; 7e33780Crossref Scopus (48) Google Scholar In this report, LA-derived oxylipins represented 70% to 80% of the total oxylipins detected in BALF of asthmatic subjects and healthy controls.8Lundstrom S.L. Yang J. Kallberg H.J. Thunberg S. Gafvelin G. Haeggstrom J.Z. et al.Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation.PLoS One. 2012; 7e33780Crossref Scopus (48) Google Scholar Thus, although dysregulation in oxylipin biosynthesis from AA and LA can be detected throughout the respiratory tract in patients with asthma, oxylipins seem to be produced in a compartmentalized manner.A second finding from the report by Johnson et al6Johnson R.K. Manke J. Campbell M. Armstrong M. Boorgula M.P. Pinheiro G. et al.Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.J Allergy Clin Immunol. 2022; 150: 965-971.e8Abstract Full Text Full Text PDF Scopus (1) Google Scholar is that asthmatic subjects were characterized by a reduction in the levels of anti-inflammatory omega-3–derived oxylipins in PC3 (Fig 1), including a reduction in the levels of hydroxy-eicosapentaenoic acid derived from EPA, as well as reductions in the levels of 19,20-dihydroxy-docosapentaenoic acid, Resolvin D5, 14-hydroxy docosahexaenoic acid, 17- hydroxy docosahexaenoic acid, and 11- hydroxy-docosahexaenoic acid derived from DHA. Interestingly, these findings were similar in subjects with moderate asthma and subjects with severe asthma who were exposed to inhaled corticosteroids, further supporting the fundamental role of oxylipins in asthma. Hence, not only are specialized proresolving mediators likely metabolized in the nasal epithelium, but potential target cell(s) could be identified by comparing nasal specimens from healthy controls with specimens from asthmatic subjects with various degrees of asthma severity.Therefore, although the findings of Johnson et al6Johnson R.K. Manke J. Campbell M. Armstrong M. Boorgula M.P. Pinheiro G. et al.Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.J Allergy Clin Immunol. 2022; 150: 965-971.e8Abstract Full Text Full Text PDF Scopus (1) Google Scholar are limited by sample size and subjects' sex, their study represents a first step toward the identification of asthma-associated bioactive lipids in readily accessible clinical samples. This will allow further investigation of dysregulated omega-6 and omega-3 metabolism in the respiratory milieu and triggers some critical questions. First, how do the levels of individual oxylipins in the nasal mucosa differ from the levels in the lower airway and lung? A study of paired samples would be very informative. Additionally, assessment of other clinical variables (nasal steroids, allergies, and upper respiratory tract infections) that may influence these values will be essential. Second, what accounts for the alterations in oxylipin levels? Do they reflect alterations in the abundance of the parent lipids? The relative abundance of omega-3 fatty acids competing with omega-6 for access to biosynthetic enzymes may define an important variable in establishing an imbalance between proinflammatory and proresolving mechanisms of inflammation. Furthermore, as some of these lipids can also signal through cognate G protein–coupled receptors, detection of a significant imbalance in parent lipids could implicate additional signaling pathways germane to disease. In contrast, dysregulation of oxylipin metabolism may reflect coordinated alteration in the expression of key biosynthetic enzymes. To this end, studies integrating gene expression9Do A.N. Chun Y. Grishina G. Grishin A. Rogers A.J. Raby B.A. et al.Network study of nasal transcriptome profiles reveals master regulator genes of asthma.J Allergy Clin Immunol. 2021; 147: 879-893Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and regulation10Cardenas A. Sordillo J.E. Rifas-Shiman S.L. Chung W. Liang L. Coull B.A. et al.The nasal methylome as a biomarker of asthma and airway inflammation in children.Nat Commun. 2019; 10: 3095Crossref PubMed Scopus (72) Google Scholar with lipidomic approaches will be invaluable. Third, what are the cellular and molecular targets of the bioactive lipids identified in this study, and what is their contribution to the pathogenesis and resolution of inflammation in asthmatic subjects? Remarkably, these questions are easily answered by investigating the nasal milieu and by comparing nasal epithelial samples with lower airway samples to identify potential common target cells.The use of nasal samples to detect bioactive lipids can advance our understanding of asthma pathobiology and inform asthma severity and endotypes. Therefore, this study and likely future studies will continue to expand our knowledge of potential targetable bioactive lipid molecules to treat and prevent airway diseases. The relative abundance of omega-6 versus omega-3 fatty acids, the relative expression of distinct oxylipin biosynthetic pathways, and patient sex are all factors that need to be considered to find new targets for more personalized therapies. Polyunsaturated fatty acids (PUFAs) are lipid mediators that can act at cognate receptors (G protein–coupled receptors) or be converted to a diverse range of bioactive oxylipins, through either nonenzymatic or enzymatic pathways. These pathways include lipoxygenase (LO), COX, and cytochrome P450 enzymes. Metabolomic studies conducted using the serum and bronchoalveolar lavage fluid (BALF) of asthmatic patients have identified PUFAs and oxylipins that contribute to the pathogenesis of asthma.1Reinke S.N. Gallart-Ayala H. Gomez C. Checa A. Fauland A. Naz S. et al.Metabolomics analysis identifies different metabotypes of asthma severity.Eur Respir J. 2017; 491601740Crossref Scopus (102) Google Scholar,2McGeachie M.J. Dahlin A. Qiu W. Croteau-Chonka D.C. Savage J. Wu A.C. et al.The metabolomics of asthma control: a promising link between genetics and disease.Immun Inflamm Dis. 2015; 3: 224-238Crossref PubMed Scopus (60) Google Scholar In particular, the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) generate specialized proresolving mediators that reportedly ameliorate respiratory symptoms in asthmatics subjects3Barnig C. Frossard N. Levy B.D. Towards targeting resolution pathways of airway inflammation in asthma.Pharmacol Ther. 2018; 186: 98-113Crossref PubMed Scopus (51) Google Scholar and likely compete with omega-6 PUFAs for enzymatic metabolism (Fig 1). Indeed, the ratio of these lipids may be relevant to asthma development, as intake of EPA and DHA from fish oil was associated with a reduced risk of asthma development in children carrying a mutation in fatty acid desaturase,4Talaei M. Sdona E. Calder P.C. Jones L.R. Emmett P.M. Granell R. et al.Intake of n-3 polyunsaturated fatty acids in childhood, FADS genotype and incident asthma.Eur Respir J. 2021; 582003633Crossref Scopus (6) Google Scholar an enzyme that generates omega-3 EPA and DHA from α-linolenic acid in addition to omega-6 arachidonic acid (AA) from linoleic acid (LA) (Fig 1). However, a layer of complexity comes from the opposing function of oxylipins derived from omega-6 PUFAs through different enzymatic pathways. For instance, metabolism of AA through the 5-, 15- and 12-LO pathways, produces proinflammatory cysteinyl-leukotrienes, 15-hydroxy-eicosatetraenoic acid, and anti-inflammatory lipoxin A4, respectively. Additionally, in the COX pathway, prostaglandin (PG)E2, PGF2α, and 15-deoxy-PGJ2 may exert proinflammatory and anti-inflammatory functions in the lung. Therefore, a comprehensive analysis of all oxylipins present in patients with asthma will be essential to understanding their contribution to asthma pathobiology and endotypes.5Kelly R.S. Mendez K.M. Huang M. Hobbs B.D. Clish C.B. Gerszten R. et al.Metabo-endotypes of asthma reveal differences in lung function: discovery and validation in two TOPMed cohorts.Am J Respir Crit Care Med. 2022; 205: 288-299Crossref Scopus (3) Google Scholar Ultimately, personalized treatment of asthma would ideally include selectively inhibiting or potentiating the enzymatic pathways leading to these potent lipid mediators. One significant barrier to understanding the role of oxylipins in asthma is the difficulty in measuring them in accessible tissue. In this issue of the Journal of Allergy and Clinical Immunology, Johnson et al6Johnson R.K. Manke J. Campbell M. Armstrong M. Boorgula M.P. Pinheiro G. et al.Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.J Allergy Clin Immunol. 2022; 150: 965-971.e8Abstract Full Text Full Text PDF Scopus (1) Google Scholar analyzed 56 oxylipins obtained from brushing the nasal cavities of 11 female subjects, including healthy subjects who did not have atopic asthma (n = 3), subjects with mild-to-moderate atopic asthma (n = 4), and subjects with severe atopic asthma (n = 4), as classified by the Global Initiative for Asthma guidelines. Although only the levels of 9,10-dihydroxy-octadecenoic acid were significantly different across the groups in this small study, principal component analysis across samples identified a reduction in the levels of omega-3–derived oxylipins and an increase in levels of omega-6–derived–oxylipins in principal component 3 (PC3) that was associated with asthma. Specifically, the omega-6–derived oxylipins found at increased levels in PC3 included 13 hydroxy-octadecadienoic acid (13-HODE), a 15-LO product of LA (Fig 1), and 13-oxooctadecadienoic acid, a product of further LA metabolism. Notably, in a prior study assessing oxylipin levels in subjects with asthma, increases in 13-HODE were detected in the bronchial wash but not in the BALF, as compared with the levels in the controls.7Larsson N. Lundstrom S.L. Pinto R. Rankin G. Karimpour M. Blomberg A. et al.Lipid mediator profiles differ between lung compartments in asthmatic and healthy humans.Eur Respir J. 2014; 43: 453-463Crossref Scopus (19) Google Scholar Furthermore, another study of oxylipins in the BALF of asthmatic subjects and controls reported increases in the levels of 15-hydroxy-eicosatetraenoic acid, 9,10-dihydroxy-octadecenoic acid, and 12,13-dihydroxy-octadecenoic acid, which are AA- and LA-derived metabolites of the 15-LO and cytochrome 450 pathways, respectively.8Lundstrom S.L. Yang J. Kallberg H.J. Thunberg S. Gafvelin G. Haeggstrom J.Z. et al.Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation.PLoS One. 2012; 7e33780Crossref Scopus (48) Google Scholar In this report, LA-derived oxylipins represented 70% to 80% of the total oxylipins detected in BALF of asthmatic subjects and healthy controls.8Lundstrom S.L. Yang J. Kallberg H.J. Thunberg S. Gafvelin G. Haeggstrom J.Z. et al.Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation.PLoS One. 2012; 7e33780Crossref Scopus (48) Google Scholar Thus, although dysregulation in oxylipin biosynthesis from AA and LA can be detected throughout the respiratory tract in patients with asthma, oxylipins seem to be produced in a compartmentalized manner. A second finding from the report by Johnson et al6Johnson R.K. Manke J. Campbell M. Armstrong M. Boorgula M.P. Pinheiro G. et al.Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.J Allergy Clin Immunol. 2022; 150: 965-971.e8Abstract Full Text Full Text PDF Scopus (1) Google Scholar is that asthmatic subjects were characterized by a reduction in the levels of anti-inflammatory omega-3–derived oxylipins in PC3 (Fig 1), including a reduction in the levels of hydroxy-eicosapentaenoic acid derived from EPA, as well as reductions in the levels of 19,20-dihydroxy-docosapentaenoic acid, Resolvin D5, 14-hydroxy docosahexaenoic acid, 17- hydroxy docosahexaenoic acid, and 11- hydroxy-docosahexaenoic acid derived from DHA. Interestingly, these findings were similar in subjects with moderate asthma and subjects with severe asthma who were exposed to inhaled corticosteroids, further supporting the fundamental role of oxylipins in asthma. Hence, not only are specialized proresolving mediators likely metabolized in the nasal epithelium, but potential target cell(s) could be identified by comparing nasal specimens from healthy controls with specimens from asthmatic subjects with various degrees of asthma severity. Therefore, although the findings of Johnson et al6Johnson R.K. Manke J. Campbell M. Armstrong M. Boorgula M.P. Pinheiro G. et al.Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjects.J Allergy Clin Immunol. 2022; 150: 965-971.e8Abstract Full Text Full Text PDF Scopus (1) Google Scholar are limited by sample size and subjects' sex, their study represents a first step toward the identification of asthma-associated bioactive lipids in readily accessible clinical samples. This will allow further investigation of dysregulated omega-6 and omega-3 metabolism in the respiratory milieu and triggers some critical questions. First, how do the levels of individual oxylipins in the nasal mucosa differ from the levels in the lower airway and lung? A study of paired samples would be very informative. Additionally, assessment of other clinical variables (nasal steroids, allergies, and upper respiratory tract infections) that may influence these values will be essential. Second, what accounts for the alterations in oxylipin levels? Do they reflect alterations in the abundance of the parent lipids? The relative abundance of omega-3 fatty acids competing with omega-6 for access to biosynthetic enzymes may define an important variable in establishing an imbalance between proinflammatory and proresolving mechanisms of inflammation. Furthermore, as some of these lipids can also signal through cognate G protein–coupled receptors, detection of a significant imbalance in parent lipids could implicate additional signaling pathways germane to disease. In contrast, dysregulation of oxylipin metabolism may reflect coordinated alteration in the expression of key biosynthetic enzymes. To this end, studies integrating gene expression9Do A.N. Chun Y. Grishina G. Grishin A. Rogers A.J. Raby B.A. et al.Network study of nasal transcriptome profiles reveals master regulator genes of asthma.J Allergy Clin Immunol. 2021; 147: 879-893Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and regulation10Cardenas A. Sordillo J.E. Rifas-Shiman S.L. Chung W. Liang L. Coull B.A. et al.The nasal methylome as a biomarker of asthma and airway inflammation in children.Nat Commun. 2019; 10: 3095Crossref PubMed Scopus (72) Google Scholar with lipidomic approaches will be invaluable. Third, what are the cellular and molecular targets of the bioactive lipids identified in this study, and what is their contribution to the pathogenesis and resolution of inflammation in asthmatic subjects? Remarkably, these questions are easily answered by investigating the nasal milieu and by comparing nasal epithelial samples with lower airway samples to identify potential common target cells. The use of nasal samples to detect bioactive lipids can advance our understanding of asthma pathobiology and inform asthma severity and endotypes. Therefore, this study and likely future studies will continue to expand our knowledge of potential targetable bioactive lipid molecules to treat and prevent airway diseases. The relative abundance of omega-6 versus omega-3 fatty acids, the relative expression of distinct oxylipin biosynthetic pathways, and patient sex are all factors that need to be considered to find new targets for more personalized therapies. Lipid mediators are detectable in the nasal epithelium and differ by asthma status in female subjectsJournal of Allergy and Clinical ImmunologyVol. 150Issue 4PreviewLipid mediators, bioactive products of polyunsaturated fatty acid metabolism, contribute to inflammation initiation and resolution in allergic diseases; however, their presence in lung-related biosamples has not been fully described. Full-Text PDF