In this study, we applied a targeted LC-MS/MS platform to systematically investigate the profile of plasma LMs in children with H1N1 infection. We demonstrated the dysregulation of eicosanoids from AA and octadecanoids from LA in H1N1 children. Furthermore, we found 12 LM species restored fully or partially to healthy level after recovery. Taken together, these findings suggest that disruptions in LM biosynthesis, especially eicosanoids, are related to H1N1 infection and clearance in children.
Bioactive lipid mediators play a crucial role in the induction and resolution of inflammation during influenza infection5,6,11. Controlled immune responses to infection and injury involve complex molecular networks and often opposing actions11. Previous studies15 revealed that human serum eicosanoids were changed in adult patients with severe H1N1 pneumonia. Here, we found that in children with H1N1 infection with mild symptoms, the n-6 PUFAs products, eicosanoids and octadecanoids, were predominantly changed. During the recovery from the illness, a number of LMs altered during H1N1 infection were fully or partially restored. For instance, the products derived from CYP pathways, such as DiHETEs, 17-HETE, 20-HETE, 12,13-EpOME, and 19,20-DiHDPA, were upregulated with H1N1and then decreased during recovery. Interestingly, the COX pathways products, PGD2, PGJ2, and TxB3, which are regarded as anti-inflammation and pro-resolution agents17–19, were reduced in children with H1N1, but regain the normal level after recovery. The exception is LTB4, which are biosynthesized by leukocytes during the inflammation20, remained low in H1N1 infection, and even after recovery. Our results suggested that during H1N1 infection, the lipid mediators, especially eicosanoids, are tightly regulated to counterbalance the severity of inflammation and maintain the physiological functions.
Inflammation is an essential host defense mechanism, required for protection against pathogenic micro-organisms and viruses. However, excessive and non-resolving inflammatory response is damaging to the host6,10. H1N1 infection triggers excessive inflammatory response in hosts and if unchecked, will lead to influenza pneumonia or other complications, including sepsis syndrome and respiratory distress syndrome21. During the process of inflammation, the lipid mediators from PUFAs, including AA, LA, EPA, and DHA, are synthesized and play a crucial role controlling inflammation and combating infectious organisms. In the early stage of inflammation, LTs and PGs are important in promoting immune response following tissue injury 7,8. PGD2 and its derivative 15d-PGJ2, are suppressed in virus-induced inflammation18. During the resolution of inflammation, the SPM with anti-inflammatory and pro-resolving actions, are produced with potent immune-regulatory actions11. In influenza infection, the DHA-derived resolvin, 17-HDHA, upregulates the production of neutralizing antibodies to the virus13, whereas PDs family members inhibit influenza virus replication via RNA export machinery12. It is worth noting that in H1N1 infection, the vicinal diols, such as 11,12-DIHETrE, 14,15-DiHETrE, 8,9-DiHETrE from AA, and other metabolites via the CYP and soluble epoxide hydrolase (sEH) pathways, are increased in children with H1N1. The CYP intermediate products, epoxyeicosatrienoic acids (EETs), are anti-inflammation but also analgesic, antifibrotic, and antihypertensive, acting in both autocrine and paracrine manner22. Their end metabolites, vicinal diols, might be used as potential biomarkers for inflammatory and related diseases.
Lastly, we compared the serum LM profiles in healthy children and adults and found that the serum LMs of children had a characteristic LM profiles with elevated DHA-derived SPM, such as 17-HDHA and 14-HDHA, as well as EPA derived metabolites. 17-HDHA, along with its down-stream NPD1/PD1, demonstrated anti-inflammatory and neuroprotective biofunctions13,23. The difference of LM distribution might be due to difference of metabolism, physiology, and nutrition status between children and adults24,25 .
In conclusion, our study revealed different serum LM profiles in children with H1N1 infection associated with inflammatory responses. We identified a number of LM species that were altered by H1N1 virus, and were restored after spontaneous recovery in children. These findings shed lights on the pathogenesis of H1N1 in children, and provided potential therapeutic tools for treatment of the disease.