Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production

Abstract

Background: It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin has been reported to be effective in animal models of acute lung injury. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. However, it is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). Therefore, in this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection. Methods: VILI was induced by high tidal volume ventilation in a rat model. The rats were randomly allotted into the following groups: control, control+melatonin, control+ramelteon, control+luzindole, VILI, VILI+luzindole, VILI + melatonin, VILI + melatonin + luzindole (melatonin receptor antagonist), VILI + ramelteon, and VILI + ramelteon + luzindole (n = 6 per group). The role of interleukin-10 (IL-10) in the melatonin-or ramelteon-mediated protection against VILI was also investigated. Results: Ramelteon treatment markedly reduced lung edema, serum malondialdehyde levels, the concentration of inflammatory cytokines in bronchoalveolar lavage fluid (BALF), NF-κB activation, iNOS levels, and apoptosis in the lung tissue. Additionally, ramelteon treatment significantly increased heat shock protein 70 expression in the lung tissue and IL-10 levels in BALF. The protective effect of ramelteon was mitigated by the administration of luzindole or an anti-IL-10 antibody. Conclusions:Our results suggest that a melatonin receptor agonist has a protective effect against VILI, and its protective mechanism is based on the upregulation of IL-10 production.

Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed

“…For instance, in a murine model, melatonin increased the level of the anti-inflammatory IL-10, along with improved oxygenation and reduced histological damage to the lungs [37]. Furthermore, a recent study using ramelteon, the melatoninergic agonist, in lung-injured rats revealed strong reductions in oxidative markers, reduced edema, neutrophil infiltration, the induction of apoptosis, decreased NF-κB activation and iNOS expression, and lower levels of TNFα, IL-1β, and IL-6 [38]. It should also be pointed out that the practical problem in patients with severe COVID-19 concerns the reduction of pulmonary gas exchange due to surfactant impairments by lipid peroxidation caused by infiltrating neutrophils.…”

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“…73,74 Furthermore, melatonin is protective against ventilator-induced lung injury in animal models. 75,76 Studies in animals and humans have found beneficial effects of melatonin against serious viral infections, including herpes, HIV/AIDS, influenza A-H1N1, West Nile virus, coxsackievirus (the virus that Witek-Janusek et al 41 Qin et al 32 2.911 2.722 IL-6 -0.386 -0.571…”

Delirium and sleep disturbances in COVID–19: a possible role for melatonin in hospitalized patients?

“…It is noteworthy that, based on its anti-inflammatory, antioxidative and immune-enhancing features, a putative effect of melatonin in alleviating infection-induced acute respiratory distress has also been proposed [4]. In animal models, this natural hormone has been shown to improve acute lung injury by acting as a direct antioxidant and via melatonin receptor activation.…”