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

Geng-Chin Wu, Chung-Kan Peng, Wen-I Liao, Hsin-Ping Pao, Kun-Lun Huang, Shi-Jye Chu, Geng-Chin Wu, Chung-Kan Peng, Wen-I Liao, Hsin-Ping Pao, Kun-Lun Huang, Shi-Jye Chu

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.

Keywords: Interleukin-10; Melatonin receptor agonist; Ramelteon; Ventilator-induced lung injury.

Conflict of interest statement

All authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Effect of melatonin and ramelteon on lung edema. VILI significantly increased the lung weight/body weight ratio (a), W/D weight ratio (b), and protein levels in BALF (c). Melatonin or ramelteon treatment significantly reduced these increases. The protective effect of melatonin and ramelteon was abrogated by luzindole treatment. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p-values < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 2
Fig. 2
Effect of melatonin and ramelteon on serum malondialdehyde (MDA) levels, carbonyl content and myeloperoxidase (MPO)-positive cell numbers in lung tissue. Serum MDA levels (a), carbonyl content (b) and MPO-positive cell numbers in lung tissue (c) were significantly increased in the VILI group. Melatonin or ramelteon treatment significantly attenuated these increases. The protective effect of melatonin and ramelteon was abrogated by luzindole treatment. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p-values < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 3
Fig. 3
Effect of melatonin and ramelteon on TNF-α, IL-1β, IL-6, and CXCL-1 concentrations in BALF. TNF-α (a), IL-1β (b), IL-6 (C), and CXCL-1 (d) levels in BALF increased significantly in the VILI group. The increases in the BALF protein concentrations were significantly attenuated by treatment with melatonin or ramelteon. The protective effect of melatonin and ramelteon was abrogated by luzindole treatment. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 4
Fig. 4
Effect of melatonin and ramelteon on IL-10 levels in BALF and STAT3 expression in the lung tissue. The p-STAT 3 level in lung tissue was determined by western blotting. β-Actin served as a loading control for cytoplasmic proteins. VILI significantly decreased IL-10 levels in BALF (a) and increased p-STAT3 protein expression in the lung tissue (b). Melatonin or ramelteon treatment significantly reversed this phenomenon. When luzindole was added, the protective effect of melatonin and ramelteon was blocked. Data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 5
Fig. 5
Effect of melatonin and ramelteon on iNOS expression. iNOS levels in the lung tissue were determined by western blotting. β-Actin served as a loading control for cytoplasmic proteins. VILI significantly increased iNOS protein expression. Melatonin or ramelteon treatment significantly attenuated the increase. When luzindole was added, the protective effect of melatonin and ramelteon was blocked. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p-values < 0.05); # significantly different from the VILI group (p < 0.05)
Fig. 6
Fig. 6
Effect of melatonin and ramelteon on lung pathology. a Hematoxylin and eosin staining analysis of lung pathological injury. Representative photomicrographs were taken at a magnification of × 400. b The numbers of neutrophils per high-power field (× 400 magnification), and c lung injury score. Histological evaluation of lung tissues showed that neutrophil infiltration and the lung injury score were increased in the VILI group. Melatonin or ramelteon treatment significantly attenuated these histopathological changes, but the protective effect of melatonin and ramelteon was abrogated by luzindole treatment. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 7
Fig. 7
Effect of melatonin and ramelteon on the NF-κB signaling pathway. a The NF-κB p65 level and b IκBα level in the lung tissue were determined by western blotting. PCNA and β-actin served as loading controls for nuclear and cytoplasmic proteins, respectively. Representative blots are shown. Melatonin or ramelteon treatment reduced NF-κB p65 levels and increased IκB-α levels in VILI. When luzindole was added, the protective effect was blocked. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 8
Fig. 8
Effect of melatonin and ramelteon on apoptosis. Hsp70 (a), Bcl-2 (b), caspase-3 (c), and cleaved PARP (d) levels in the lung tissue were determined by western blotting. Melatonin or ramelteon treatment increased Hsp70 and Bcl-2 levels and reduced caspase-3 and cleaved PARP levels in VILI. When luzindole was added, the protective effect was blocked. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 9
Fig. 9
Effect of an anti-IL-10 antibody on melatonin- and ramelteon-mediated BALF IL-10 levels. VILI significantly decreased IL-10 levels in BALF. Melatonin or ramelteon treatment significantly reversed this phenomenon. When an anti-IL-10 antibody was administered, the protective effect of melatonin and ramelteon was blocked. Data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p #significantly different from the VILI group (p < 0.05)
Fig. 10
Fig. 10
Effect of anti-IL-10 antibody on melatonin- and ramelteon-mediated VILI protection against lung edema. a Lung weight/body weight ratio. b W/D weight ratio. c Protein levels in BALF. Melatonin or ramelteon treatment significantly attenuated the increase in LW/BW and W/D weight ratios and protein levels in VILI. When an anti-IL-10 antibody was administered, the protective effect was blocked. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 11
Fig. 11
Effect of an anti-IL-10 antibody on the melatonin- and ramelteon-mediated cytokines concentrations in BALF. TNF-α (a), IL-1β (b), and IL-6 (c) levels in BALF increased significantly in the VILI group. The increases in the BALF protein concentrations were significantly attenuated by treatment with melatonin or ramelteon. The protective effect of melatonin and ramelteon was abrogated by anti-IL-10 antibody treatment. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 12
Fig. 12
Effect of an anti-IL-10 antibody on the melatonin- and ramelteon-mediated lung pathology. a Hematoxylin and eosin staining analysis of lung pathological injury. b The numbers of neutrophils per high-power field, and c lung injury score. Representative photomicrographs were taken at a magnification of × 400. Histological evaluation of lung tissues showed that neutrophil infiltration and the lung injury score were increased in the VILI group. Melatonin or ramelteon treatment significantly attenuated these histopathological changes, but the protective effect of melatonin and ramelteon was abrogated by anti-IL-10 antibody treatment. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)
Fig. 13
Fig. 13
Effect of an anti-IL-10 antibody on the melatonin- and ramelteon-mediated apoptosis and NF-κB signaling pathway. a Bcl2, b cleaved PARP,and c NF-κB p65 levels in the lung tissue were determined by western blotting. Lamin B and β-actin served as loading controls for nuclear and cytoplasmic proteins, respectively. Melatonin or ramelteon treatment increased Bcl2, and reduced cleaved PARP and NF-κB p65 levels in VILI. When anti-IL-10 antibody was added, the protective effect was blocked. The data are expressed as the mean ± SD (n = 6 per group). *Significantly different from the control (p < 0.05); #significantly different from the VILI group (p < 0.05)

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