Introduction: Sleep disturbances are assumed to impair health through induction of low-grade systemic inflammation. Experimental studies have shown that such inflammatory upregulation does not normalize even after a couple of nights of recovery sleep. We hypothesized that sleep disturbances do not only affect inflammatory pathways, but also the recently detected inflammatory resolution pathways, which actively terminate inflammation. Mediators of inflammatory resolution mainly derive from omega-3 fatty acids converted to specialized pro-resolving mediators (SPMs), such as resolvins. We investigated SPMs in healthy humans exposed to a novel model of experimental insomnia.

Methods: Twenty-four individuals (age 18-42 years, 12 women) participated in a study consisting of two 19-day in-hospital protocols (insomnia/control). After three nights of baseline sleep (8h/night, 23:00-07:00), participants in the experimental insomnia condition were exposed to three cycles of three nights of disturbed sleep (delayed sleep-onset, hourly sleep disruption, advanced sleep-offset) followed by one night of 8h-recovery sleep. The protocol ended with three additional nights of recovery sleep. In the control condition, participants had an uninterrupted sleep opportunity (8h/night) across the 19-day protocol. Blood samples were taken at 11:00 at baseline, during experimental insomnia exposure, and after recovery sleep. Several SPMs were measured in plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data were analyzed using linear mixed models.

Results: Exposure to experimental insomnia affected several SPMs compared to control sleep, including a decrease of resolvin D4 and E2 concentrations, which was still evident after the third recovery night (p<.05).

Conclusion: This is the first investigation on the effects of experimentally induced sleep disturbance on inflammatory resolution pathways. The results support that SPMs, particularly resolvin D4 and E2, are decreased by sleep disturbances, and do not normalize after a couple of nights of recovery sleep. Targeting these pathways by pharmacologically increasing SPMs may help to limit inflammatory consequences of sleep disturbances. Support: NIH/NINDS R01-NS091177; NIH/National Center for Research Resources UL1-RR02758 and M01-RR01032 to the Harvard Clinical and Translational Science Center.