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Environmental exposures: another effect on sphingolipids in asthma?

Classifying the heterogeneity of asthma has been an ongoing challenge. Asthma phenotypes and endotypes have mainly been defined by clinical features, markers of atopy, airway immune cells and inflammatory markers. While clustering has helped the advancement of biologics specific targeting immune receptors or IgE, there has been less success in using clustering by other parameters such as genetics or environmental factors therapeutically. Despite a wealth of information on the detrimental effects of environmental factors such as air pollution and tobacco smoke exposure on asthma, their role in asthma pathogenesis is still unclear. The integration of environmental factors in host metabolic and inflammatory endotypes is of great interest and poorly understood. The study by Wu and colleagues addresses this gap in knowledge by evaluating environmental exposures to small particulate matter (PM2.5) in six asthma endotypes from a data base of adults with asthma in Taiwan that included 209 837 emergency and 638 538 outpatient visits. In a casecontrol study, the authors further assessed markers for pollutant exposure and oxidative stress as well as metal concentrations in urine, blood cytokines and sphingolipids in adults with (n=365) and without (n=235) asthma. Monitoring urinary markers of effect of environmental exposures as a measure of the body burden has been a valuable tool for assessing pollutant exposure and risk. Specifically, the researchers quantified several biomarkers of exposure, such as metals, and biomarkers of effect of exposure to polyaromatic hydrocarbons, such oxidative stress markers, in the urine. Cytokines and two bioactive sphingolipids, sphingosine1phosphate (S1P) and ceramide1phosphate (C1P) were evaluated in the plasma. S1P and C1P were selected for analysis based on the hypothesis that exposure to polyaromatic hydrocarbons induces asthmarelevant effects on sphingolipids, mainly increases in S1P, which they had seen experimentally through the action aryl hydrocarbon receptors. The results show that S1P and C1P were both higher in asthma subjects. S1P correlated with the urinary 1hydroxypyrene in asthmatic subjects and 1,3butadiene in the controls, whereas increased C1P correlated with urinary heavy metals. Interestingly, there was no correlation between these two sphingolipids to lung function parameters, blood IgE or eosinophils. The authors conclude that environmental pollutants, including metals, polyaromatic hydrocarbons and 1,3butadiene, may be helpful to distinguish the risk and severity signatures for asthma and that these signatures, including the elevated S1P and C1P, could define a novel asthma endotype. These results and the potential new asthma endotype are of great interest and will inform future studies. However, several potential weaknesses in the current study design are worth mentioning: the allergy status in the study by Wu et al was characterised mainly through selfreporting and total IgE levels, which may lead to mischaracterization of this critical asthma feature as sphingolipid levels may differ in atopic and nonatopic subjects. Medication may be another confounding factor. While all subjects were asked to stop all medications 3 days before the sample collection, this was not monitored. Biologics or steroids could have effects that persist for longer than 3 days, especially in urine. Other confounding factors may have been the difference in body mass index between cases and controls. As the authors also point out, the study population was from a metropolitan area with high air pollution, which could affect the generalisability of the findings. Nevertheless, this study adds important information to the still enigmatic role that sphingolipids may have in asthma. Common 17q21 genetic variations are known to change the expression of the sphingolipid regulator ORMDL3, a key inhibitor of sphingolipid synthesis. This has led to several studies demonstrating that children with asthmaassociated genotypes have lower blood levels of sphingolipids mainly produced by de novo synthesis and this also reflected nasal gene expression of sphingolipid synthesisassociated genes. These studies analysed a larger number of sphingolipids using mass spectrometry. They did not primarily focus on the bioactive sphingolipids S1P and C1P that can also reliably be measured by ELISA, as was done in the present study. Especially for S1P, elevated levels would be expected in inflammatory conditions such as asthma with oxidative stress, and S1P can also lead to bronchoconstriction via stimulation of S1P receptors. Less is known about the asthmaspecific effects of C1P. The authors also postulate a direct ORMDL3associated effect by inhibiting S1P lyase, the enzyme that irreversibly degrades S1P, through an interaction of polyaromatic hydrocarbons with aryl hydrocarbon receptors. This mechanism could explain the increased S1P together with ORMDL3’s known inhibitory effect on sphingolipid de novo synthesis. It would be interesting also to evaluate the 17q21 genetics in this cohort and to assess if there is an additional effect on sphingolipids derived from de novo synthesis. Increased oxidative stress is postulated as the underlying driver of this asthma endotype by direct effects of air particle components generating oxidative stress resulting in inflammation and eventually leading to tissue remodelling, in the case of asthma, mostly in the airways. For other chronic inflammatory conditions such as atherosclerosis, plasma sphingolipids were also increased with PM2.5 exposure and possibly mediating proatherogenic effects. Increased oxidative stress increases sphingolipid metabolism, generating bioactive lipid metabolites and key signalling mediators, mainly studied for chronic obstructive pulmonary disease (COPD) and less for asthma. Subjects with COPD and asthma were excluded from this study. This study contributes significantly to our understanding if and how sphingolipids are involved in asthma pathogenesis. It adds air environmental pollution exposure to the list of factors that need to be considered, besides genetics, atopy and viral triggers, and highlight bioactive sphingolipids in asthma as markers and as potentially therapeutic targets.