Metabolomics of asthma
2014; Elsevier BV; Volume: 133; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2014.02.010
ISSN1097-6825
Autores Tópico(s)Metabolomics and Mass Spectrometry Studies
ResumoTwo recent publications in this Journal provide interesting reading regarding the metabolomics of asthma. Fitzpatrick et al1Fitzpatrick A.M. Park Y. Brown L.A.S. Jones D.P. Children with severe asthma have unique oxidative stress–associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e8Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar and Loureiro et al2Loureiro C.C. Duarte I.F. Gomes J. Carrola J. Barros A.S. Gil A.M. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e5Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar identified metabolites and metabolic pathways suggesting that oxidative stress is a factor contributing to asthma severity in children and asthma exacerbation in adults, respectively. Although these findings support a role for oxidative stress in asthmatic patients, these studies have some limitations. Because of the design of the studies, it is not clear whether the reported and highlighted metabolites are a proxy for oxidative stress contributing to severe asthma and asthma exacerbation or a consequence of the disease. It is also not completely clear whether the findings are driven by use of medication; this is common to both studies but particularly relevant in the study by Loureiro et al2Loureiro C.C. Duarte I.F. Gomes J. Carrola J. Barros A.S. Gil A.M. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e5Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar because samples from the exacerbation period were collected after the treatment provided at the emergency department. The 2 groups of children from the study by Fitzpatrick et al1Fitzpatrick A.M. Park Y. Brown L.A.S. Jones D.P. Children with severe asthma have unique oxidative stress–associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e8Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar are not totally comparable because the group with severe asthma was almost exclusively nonwhite, unlike the control group (mild asthma), and because racial differences in biological predictors of severe asthma have been reported.3Gamble C. Talbott E. Youk A. Holguin F. Pitt B. Silveira L. et al.Racial differences in biologic predictors of severe asthma: data from the Severe Asthma Research Program.J Allergy Clin Immunol. 2010; 126: 1149-1156.e1Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar In addition, the use of nonfasting samples raises the question of whether the results might have been influenced by diet because several food items have been shown to associate with specific metabolites4Floegel A. von Ruesten A. Drogan D. Schulze M.B. Prehn C. Adamski J. et al.Variation of serum metabolites related to habitual diet: a targeted metabolomic approach in EPIC-Potsdam.Eur J Clin Nutr. 2013; 67: 1100-1108Crossref PubMed Scopus (91) Google Scholar and the short-term effects of diet on the metabolome are uncertain. Finally, like most of the previous studies on the metabolomics of asthma (Table I), these were pilot studies (small by nature) that could not adjust for potential confounders.Table ISummary of previous publications on the metabolomics of asthma and their main findings and issuesReference (y)Study populationType of sampleAnalytical methodMain findingsMain issuesChildren Carraro et al (2007)E1Carraro S. Rezzi S. Reniero F. Heberger K. Giordano G. Zanconato S. et al.Metabolomics applied to exhaled breath condensate in childhood asthma.Am J Respir Crit Care Med. 2007; 175: 986-990Crossref PubMed Scopus (199) Google Scholar•25 asthmatic patients (17 with persistent asthma treated with ICSs; 8 with intermittent asthma with no ICSs in previous month)•11 healthy age-matched control subjectsExhaled breath condensateNMR•Acetylated products (1.7-2.2 ppm spectral region) and oxidized compounds (3.2-3.4 ppm spectral region) discriminated asthmatic from nonasthmatic subjects•Small sample size•Not clear what metabolites have been identified•Role of ICSs in findings not clear Saude et al (2011)E2Saude E.J. Skappak C.D. Regush S. Cook K. Ben-Zvi A. Becker A. et al.Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy.J Allergy Clin Immunol. 2011; 127 (e1-6): 757-764Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar•73 with stable atopic asthma, 67% with ICSs•20 with unstable asthma in emergency department, 50% with ICSs•42 healthy age and sex matched (10 confirmed nonatopic)UrineNMR•Several metabolites from several pathways discriminated asthma exacerbation from stable asthma•Small sample size•Role of ICSs in findings not clear•Treatment given at emergency department not mentioned Mattarucchi et al (2012)E3Mattarucchi E. Baraldi E. Guillou C. Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites.Biomed Chromatogr. 2012; 26: 89-94Crossref PubMed Scopus (76) Google Scholar•41 atopic asthmatic patients (14 with SABAs; 16 with low-concentration ICSs + LABAs; 11 with high-concentration ICSs + LABAs)•12 age-matched nonatopic nonasthmatic subjectsUrineLC-MS•Low levels of urocanic acid, methyl-imidazoleacetic acid, and a metabolite like isoleucyl-proline in asthmatic patients•Small sample size•Role of ICSs in findings not clear Sinha et al (2012)E4Sinha A. Krishnan V. Sethi T. Roy S. Ghosh B. Lodha R. et al.Metabolomic signatures in nuclear magnetic resonance spectra of exhaled breath condensate identify asthma.Eur Respir J. 2012; 39: 500-502Crossref PubMed Scopus (26) Google Scholar•58 asthmatic patients•2 healthy nonasthmatic subjectsExhaled breath condensateNMR•Asthmatic patients showed lack of ammonium ions•Small sample size•No mention of use of ICSs or any other treatment Carraro et al (2013)E5Carraro S. Giordano G. Reniero F. Carpi D. Stocchero M. Sterk P.J. et al.Asthma severity in childhood and metabolomic profiling of breath condensate.Allergy. 2013; 68: 110-117Crossref PubMed Scopus (99) Google Scholar•42 atopic asthmatic patients (31 with nonsevere asthma [17 with low- to medium-concentration ICSs alone or combined with LABAs mainly; 14 ICS naive); 11 with severe asthma with high-concentration ICSs (and others) + LABAs]•15 healthy subjectsExhaled breath condensateNMR•High levels of retinoic acid– and deoxyadenosine-related metabolites in patients with severe asthma•Low levels of ercalcitriol in patients with severe asthma•Low levels of 20-hydroxy-prostaglandin F2a, 6-keto-prostaglandin F1a, and thromboxane B2 in patients with severe asthma•Small sample size•Role of ICSs in findings not clear Gahleitner et al (2013)E6Gahleitner F. Guallar-Hoyas C. Beardsmore C.S. Pandya H.C. Thomas C.P. Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath.Bioanalysis. 2013; 5: 2239-2247Crossref PubMed Scopus (48) Google Scholar•25 asthmatic patients (17 with persistent asthma treated with ICSs; 8 with intermittent asthma with no ICSs in previous month)•11 healthy age-matched control subjectsExhaled breath condensate (fasting)GC-MS•Eight metabolites discriminated asthmatic patients from healthy children: 1-(methylsulfanyl)propane, ethylbenzene, 1,4-dichlorobenzene, 4-isopropenyl-1-methylcyclohexene, 2-octenal, octadecyne, 1-isopropyl-3-methylbenzene, and 1,7-dimethylnaphtalene•Small sample size•Role of ICSs in findings not clearAdults Sinha et al (2012)E4Sinha A. Krishnan V. Sethi T. Roy S. Ghosh B. Lodha R. et al.Metabolomic signatures in nuclear magnetic resonance spectra of exhaled breath condensate identify asthma.Eur Respir J. 2012; 39: 500-502Crossref PubMed Scopus (26) Google Scholar•7 asthmatic patients (nonsmokers)•10 healthy nonasthmatic subjects (nonsmokers)Exhaled breath condensateNMR•Lack of ammonium ions in asthmatic patients•Small sample size•No mention of use of ICSs or any other treatment Ibrahim et al (2013)E7Ibrahim B. Marsden P. Smith J.A. Custovic A. Nilsson M. Fowler S.J. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma.Allergy. 2013; 68: 1050-1056Crossref PubMed Scopus (43) Google Scholar•79 asthmatic patients (77% with ICSs)•34 control subjectsExhaled breath condensateNMR•Five spectral regions distinguished asthmatic patients from control subjects (AUC = 0.91)•Small sample size•Role of ICSs in findings not clear•Control subjects were approximately 14 y younger than asthmatic patients Jung et al (2013)E8Jung J. Kim S.H. Lee H.S. Choi G.S. Jung Y.S. Ryu D.H. et al.Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis.Clin Exp Allergy. 2013; 43: 425-433Crossref PubMed Scopus (117) Google Scholar•39 asthmatic patients (77% with ICSs; they stopped their medication for ≥3 d before sample collection; 44% were atopic)•26 healthy control subjectsSerumNMR•High levels of methionine, glutamine, and histidine and lower levels of formate, methanol, acetate, choline, O-phosphocholine, arginine, and glucose in asthmatic patients•Small sample size•Medication stopped 3 d before sample collection, but ICS-related DNA methylation effect should not be excluded Loureiro et al (2013)E9Loureiro C.C. Caldeira M. Rocha S. Todo-Bom A. Loureiro M. Metabolomic applied to omalizumab effect in severe asthmatics—a preliminary result.Clin Transl Allergy. 2013; 3: P26Crossref PubMed Google Scholar•Woman with severe persistent allergic asthma treated with omalizumabUrineGC-MS•Previous to treatment, main metabolites were alkanes; 12 weeks after, aldehydes were main metabolites•Just 1 case Ried et al (2013)E10Ried J.S. Baurecht H. Stuckler F. Krumsiek J. Gieger C. Heinrich J. et al.Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma.Allergy. 2013; 68: 629-636Crossref PubMed Scopus (62) Google Scholar•260 asthmatic patients from the KORA cohort (asthmatic patients with 3 definitions: 260 patients with asthma ever; 147 nonmedicated patients with current asthma; 104 medicated asthmatic patients)•2778 patients with asthma never (control subjects)Serum (fasting)ESI-MS/MS•High levels of phosphatidylcholines and low levels of lyso-phosphatidylcholines in patients with current asthma (similar results for medicated asthma)•Changes in levels of polyunsaturated phosphatidylcholines were associated with asthma and affected by asthma risk alleles (in PSMD3 and MED24)•Causality could not be establishedFor a full list of citations in this table, see this article's Online Repository at www.jacionline.org.AUC, Area under the curve; ESI-MS/MS, electrospray ionization tandem mass spectrometry; GC-MS, gas chromatography mass spectrometry; ICS, inhaled corticosteroid; KORA, Kooperative Gesundheitsforschung in der Region Augsburg; LABA, long-acting β-agonist; LC-MS, liquid chromatography mass spectrometry; NMR, nuclear magnetic resonance; SABA, short-acting β-agonist. Open table in a new tab For a full list of citations in this table, see this article's Online Repository at www.jacionline.org. AUC, Area under the curve; ESI-MS/MS, electrospray ionization tandem mass spectrometry; GC-MS, gas chromatography mass spectrometry; ICS, inhaled corticosteroid; KORA, Kooperative Gesundheitsforschung in der Region Augsburg; LABA, long-acting β-agonist; LC-MS, liquid chromatography mass spectrometry; NMR, nuclear magnetic resonance; SABA, short-acting β-agonist. The studies by Fitzpatrick et al1Fitzpatrick A.M. Park Y. Brown L.A.S. Jones D.P. Children with severe asthma have unique oxidative stress–associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e8Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar and Loureiro et al,2Loureiro C.C. Duarte I.F. Gomes J. Carrola J. Barros A.S. Gil A.M. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e5Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar together with previous studies, have shown several metabolites and pointed out several pathways that could characterize asthma or asthma exacerbations. Not all studies used the same methods (some used nuclear magnetic resonance and others used mass spectrometry) or sample types (some used serum and others used urine or exhaled breath condensate), collected fasting samples, or controlled for the use of asthma-related and non–asthma-related drugs or comorbidities. This should remind us of what we have seen when large genome-wide association studies did not replicate tens of single nucleotide polymorphisms that were previously found to be associated with disease in small candidate gene studies. Nevertheless, the present findings, as those from previous studies, are excellent candidate metabolites to be replicated in future and larger studies. In summary, on the basis of the publications by Fitzpatrick et al1Fitzpatrick A.M. Park Y. Brown L.A.S. Jones D.P. Children with severe asthma have unique oxidative stress–associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e8Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar and Loureiro et al,2Loureiro C.C. Duarte I.F. Gomes J. Carrola J. Barros A.S. Gil A.M. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e5Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar some might conclude that we have enough information to move to the development of treatments targeting the oxidative stress–related pathways. Unfortunately, we are still far from understanding the real meaning of these metabolites, and we cannot exclude that some of the current findings might be false-positive results that will not be replicated in larger and better controlled studies. Randomized trials and animal model studies showing the effects of controller drugs on the metabolic profile should provide important information that will help to disentangle the effect of such drugs on the metabolome. Children with severe asthma have unique oxidative stress–associated metabolomic profilesJournal of Allergy and Clinical ImmunologyVol. 133Issue 1PreviewChildren with severe asthma are a challenging group of patients who are extremely difficult to treat. Although inhaled corticosteroids (ICS) are the cornerstone of asthma treatment, children with severe asthma have decreased responsiveness to high-dose corticosteroid therapy1 associated with airway inflammation and remodeling.2 Given the limited efficacy of corticosteroids in severe asthma, our efforts have focused on the role of oxidative stress, namely, thiol redox disturbances, in the modulation of the disorder. Full-Text PDF Urinary metabolomic changes as a predictive biomarker of asthma exacerbationJournal of Allergy and Clinical ImmunologyVol. 133Issue 1PreviewExacerbations requiring hospitalization represent a high risk in patients with severe asthma. Predictive biomarkers of exacerbations are needed but are not available. Oxidative stress resulting from pulmonary reactive oxygen species formation is involved in asthma, leading to physiologic damage.1 Asthma exacerbation is associated with increased oxidative stress,2 with increased levels of carbon monoxide, nitric oxide, nitrotyrosine, and H2O2 found in breath condensate. Aldehydes and alkanes, the end products of lipid peroxidation, are also known to be involved in asthma-related oxidative stress. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 133Issue 5PreviewAmaral1 has raised some important questions that we are pleased to address regarding our recent work on the urinary metabolic profile of patients with exacerbated asthma.2 Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 133Issue 5PreviewThe correspondence from Amaral1 raises important methodological issues associated with metabolomic studies of asthma. Although such studies might identify novel pathways for drug discovery, a primary challenge that remains in the field is the curation of the metabolome because most of the chemicals detected by using high-resolution metabolomics are presently uncharacterized. To this point, we believe there is a critical need for a reference database of high-resolution metabolomic data for healthy subjects. Full-Text PDF
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