Abstract
BackgroundIt 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.MethodsVILI 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.ResultsRamelteon 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.ConclusionsOur 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.
Highlights
It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs
Effect of melatonin and ramelteon on lung edema As shown in Fig. 1a-c, the lung weight/body weight (LW/BW) and W/D weight ratios and the protein levels in bronchoalveolar lavage fluid (BALF) were significantly increased in the ventilator-induced lung injury (VILI) group compared to the control group
This study demonstrated that VILI significantly increased lung edema, neutrophil infiltration, inflammatory cytokine production, oxidative stress, apoptosis, inhibitor of NF-κB (IκB)-α degradation, nuclear translocation of Nuclear factor-κB (NF-κB), and tissue injury
Summary
It is well known that ventilation with high volume or pressure may damage healthy lungs or worsen injured lungs. Melatonin exerts its beneficial effects by acting as a direct antioxidant and via melatonin receptor activation. It is not clear whether melatonin receptor agonist has a protective effect in ventilator-induced lung injury (VILI). In this study, we determined whether ramelteon (a melatonin receptor agonist) can attenuate VILI and explore the possible mechanism for protection. Multiple studies have aimed to determine the mechanisms of ARDS and reduce mortality rates. Only lung-protective ventilation strategies with low tidal volume ventilation have been shown to reduce mortality in ARDS patients. High ventilation pressures and high tidal volumes to maintain proper oxygenation and CO2 elimination can cause lung damage and impair gas exchange. There is an urgent need to develop novel therapies for VILI
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