[Protective effects of melatonin in acute lung injury rats caused by LPS].
Dong Yu-Jie,Ding Chun-Hua,Zhang Zhi,Gu Wei-Wei,Ma Yun-Lei
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
OBJECTIVE:To observe the expression of p-p38 mitogen-activated protein kinase in lung tissues of acute lung injury rat model induced by lipopolysaccharide (LPS) and to explore the protective effects of melatonin (MT) in lung tissues in rats. METHODS:Seventy-two rats was randomly assigned to three groups, control group, LPS group and LPS + MT group. Rat model of ALI was established by instilling LPS intratracheally. We used immunohistochemical SP and Western blot method to detect the expression of p-p38 mitogen-activated protein kinase in lung tissues and used light microscope to observe morphological changes. RESULTS:There were rare p-p38 mitogen-activated protein kinase positive cells scattered in alveolar and airway epithelial cells in control group (P < 0.01). The positive p-p38 mitogen-activated protein kinase cells in LPS group increased obviously than those in control group (P < 0.01), and were mainly distributed in infiltrative inflammatory cells, airway epithelial cells, alveolar epithelial cells and pleurames epithelial cells. In MT group, the p-p38 mitogen-activated protein kinase positive cells in airway and lung tissues were much less than those in the LPS group (P < 0.05). The Western blot results were consistent with those of immunohistochemical method. CONCLUSION:The expression of p-p38 mitogen-activated protein kinase increases in alveolar and airway epithelial cells in acute lung injury rat models induced by LPS. The activation of p-p38 mitogen-activated protein kinase is found in most lung tissues, suggesting that p-p38 mitogen-activated protein kinase participates in the signal transduction in inflammatory and noninflammatory cells. MT is an effective antioxidant, which relieves the inflammation in acute lung injury rats, possibly through the inhibition of the pathway of p38 MAPK over activation.
Melatonin attenuates phosgene-induced acute lung injury via the upregulation Wnt/β-catenin pathway.
Zhang Lin,Zhang Feng,He Daikun,Xu Daojian,Zhong Zhiyue,Shen Jie
International journal of clinical and experimental pathology
The aim of this study was to assess the therapeutic effect of melatonin in phosgene induced acute lung injury (ALI) and to explore the related mechanisms. A rat model of phosgene induced ALI was established and the severity of the ALI was evaluated by wet/dry (W:D) ratio of lung weight, bronchoalveolar lavage (BAL) fluid cell counts and inflammatory cytokines. The rats were administrated with elatonin (MT), ulinastatin (UTI), p38 inhibitor and NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) alone or in combination. We found that MT in combination with UTI significantly improved the severity of ALI and the activation of Wnt/β-catenin signaling was involved in beneficial effect of MT. MT may be used as a therapeutic adjuvant for phosgene induced ALI.
[Protective function of melatonin to acute lung injury and its mechanisms in rats caused by oleic acid].
Zhang Zhi,Gao Lei,Ding Chun-Hua,Ma Wen-Zhe,Gu Wei-Wei,Ma Yun-Lei
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology
OBJECTIVE:To observe the expression of P-selectin (Ps), intercellular adhesion molecule-1 (ICAM-1) and nuclear factor-kappa B (NF-kappaB) in lung tissues of acute lung injury (ALI) rat model induced by oleic acid (OA) and to explore the protective effects of melatonin (MT) in lung tissues in rats. METHODS:All rats were randomly divided into four groups: control group, OA group, MT + OA group and SB203580 + OA group. Rat model of ALI was established by intravenous injection of oleic acid (OA). Lung coefficient was measured, lung tissues were imbedded by paraffin to observe morphological changes and the expression of Ps, ICAM-1 and NF-kappaB in lung tissues by means of immunohistochemistry staining. RESULTS:Compared with control group, the lung coefficient increased significantly in OA group (P < 0.05). Alveolar septum thickened significantly in OA group, there had many infiltrated inflammatory cells and collapsed alveoli of lung; positive expression of Ps, ICAM-1 and NF-kappaB were very obvious (P < 0.05); the administration of MT and SB203580 mitigated above changes significantly (P < 0.05). CONCLUSION:MT possesses obviously protective effect on lung tissues during ALI, its protective mechanism might be related to the inhibition of the expression of Ps, ICAM-1 and NF-kappaB.
Dietary melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway.
Han Bing,Li Siyu,Lv Yueying,Yang Daqian,Li Jiayi,Yang Qingyue,Wu Pengfei,Lv Zhanjun,Zhang Zhigang
Food & function
Exposure to chromium (Cr) causes a number of respiratory diseases, including lung cancer and pulmonary fibrosis. However, there is currently no safe treatment for Cr-induced lung damage. Here, we used in vivo and in vitro approaches to examine the protective effects of melatonin (MEL) on Cr-induced lung injury and to identify the underlying molecular mechanisms. We found that treatment of rats or a mouse lung epithelial cell MLE-12 with MEL attenuated KCrO-induced lung injury by reducing the production of oxidative stress and inflammatory mediators and inhibiting cell apoptosis. MEL treatment upregulated the expression of silent information regulator 1 (Sirt1), which deacetylated the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α). In turn, this increased the expression of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and key anti-oxidant target genes. These results suggest that melatonin attenuates chromium-induced lung injury via activating the Sirt1/Pgc-1α/Nrf2 pathway. Dietary MEL supplement may be a potential new strategy for the treatment of Cr poisoning.
Melatonin Alleviates Radiation-Induced Lung Injury via Regulation of miR-30e/NLRP3 Axis.
Wu Xu,Ji Haiying,Wang Yuli,Gu Chenlin,Gu Wenyu,Hu Lijuan,Zhu Lei
Oxidative medicine and cellular longevity
Melatonin is a well-known anti-inflammatory and antioxidant molecule, which plays a crucial role in various physiological functions. In this study, mice received a single dose of 15 Gy radiation delivered to the lungs and daily intraperitoneal administration of melatonin. After 7 days, mice were processed to harvest either bronchoalveolar lavage fluid for cytokine assays or lungs for flow cytometry and histopathological studies. Herein, we showed that melatonin markedly alleviated the oxidative stress and injury, especially suppressing the infiltration of macrophages (CD11b+CD11c-) and neutrophils (CD11b+Ly6G+) to the irradiated lungs. Moreover, in the irradiated RAW 264.7 cells, melatonin blocked the NLRP3 inflammasome activation accompanied with the inhibition of the IL-1 release and caspase-1 activity. However, melatonin restored the downregulated miR-30e levels. Quantitative PCR analysis of miR-30e and NLRP3 indicated the negative correlation between them. Notably, immunofluorescence staining showed that overexpression of miR-30e dramatically diminished the increased NLRP3 expression. Luciferase reporter assay confirmed that NLRP3 was a target gene of miR-30e. Western blotting revealed that transfection with miR-30e mimics markedly reduced the expressions of NLRP3 and cleaved caspase-1, whereas this phenomenon was reversed by the miR-30e inhibitor. Consistent with this, the beneficial effect of melatonin under irradiated exposure was blunted in cells transfected with anti-miR-30e. Collectively, our results demonstrate that the NLRP3 inflammasome contributed to the pathogenesis of radiation-induced lung injury. Meanwhile, melatonin exerted its protective effect through negatively regulating the NLRP3 inflammasome in macrophages. The melatonin-mediated miR-30e/NLRP3 signaling may provide novel therapeutic targets for radiation-induced injury.
Melatonin prevents lung injury induced by hepatic ischemia-reperfusion through anti-inflammatory and anti-apoptosis effects.
Zhou Li,Zhao Dong,An Haiyan,Zhang Hong,Jiang Chunling,Yang Baxian
Melatonin is a free radical scavenger and broad-spectrum antioxidant with immunomodulatory effects. The objective of the study is to investigate the effects of melatonin in hepatic ischemia/reperfusion (I/R) induced lung injury and explore its underlying mechanisms. Hepatic I/R injury was induced via portal vein and hepatic artery occlusion for 30min followed by 3-h reperfusion. Male Sprague-Dawley rats were divided into three groups: sham, I/R+ Vehicle and I/R+melatonin. Melatonin (10mg/kg) or vehicle was injected intravenously 15min before ischemia and 10min before reperfusion. The histology of the liver and lung, plasma aminotransferase and cytokine secretion, and apoptosis in the lung were evaluated. The phosphorylation of JNK, p38, and NF-ƙB and Nrf2 nuclear translocation in the lung was examined by Western blotting. We found that melatonin administration significantly attenuated hepatic I/R induced lung injury in rats. Melatonin inhibited the pro-inflammatory responses and enhanced antioxidative responses. Melatonin alleviated pathological changes of the lung and liver, and inhibited apoptosis of cells in the lung. Phosphorylation of JNK, p38 and NF-ƙB and Nrf2 nuclear translocation was increased significantly in the lung by hepatic I/R. Melatonin administration inhibited the activation of JNK, p38, and NF-ƙB, however, melatonin further enhanced Nrf2 activation. We conclude that melatonin exerts a protective effect in hepatic I/R induced lung injury by attenuating the pro-inflammatory responses, inhibiting cell apoptosis, which was mediated in part through JNK, p38 MAPK, NF-ƙB and Nrf2 signaling pathways. Melatonin may be a promising therapeutic strategy for hepatic I/R induced lung injury.
Melatonin treatment prevents carbon tetrachloride-induced acute lung injury in rats by mitigating tissue antioxidant capacity and inflammatory response.
Radovic M,Ristic L,Krtinic D,Rancic M,Nickovic V,Vujnovic Zivkovic Z N,Zivkovic J B,Mirkovic M V,Toskic D R,Sokolovic D
Bratislavske lekarske listy
AIM:Carbon tetrachloride (CCl4) is an organic chemical that produces different tissue‑damaging effects when ingested or inhaled. Present study aims to determine whether the application of exogenous melatonin, a neurohormone with numerous biological properties, can prevent disturbances in lung tissue antioxidative capacities and arginine metabolism, tissue inflammation and oxidative damage induced by exposure to CCl4 in rats. METHODS:The effects of melatonin on the changes occurring in rat lung tissue after an acute exposure to CCl4 were studied by monitoring alterations in antioxidant capacities, inflammatory parameters, parameters of arginine metabolism, and lipid and protein oxidative damage. RESULTS:The results indicated that melatonin prevents CCl4-induced lung damage by mitigating tissue antioxidant capacity and preventing nitric oxide production through a shift from nitric oxide synthase to arginase. Also, melatonin partially prevented tissue inflammation and molecules' oxidative modification seen after exposure to CCl4. CONCLUSIONS:The protective activity of melatonin can be attributed to its ability to scavenge both free radicals, as well as to its potential to increase tissue antioxidant capacity. The modulation of inflammatory response through both decrease in tissue inflammatory parameters and influence on arginine-nitric oxide metabolism might be an additional mechanism of action (Tab. 1, Fig. 2, Ref. 33).
Melatonin receptor agonist protects against acute lung injury induced by ventilator through up-regulation of IL-10 production.
Wu Geng-Chin,Peng Chung-Kan,Liao Wen-I,Pao Hsin-Ping,Huang Kun-Lun,Chu Shi-Jye
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.
Effects of Exogenous Melatonin on MAM Induced Lung Injury and Lung Development in Mice Offspring.
Azizi Maryam,Pasbakhsh Parichehr,Sadr Makan,Mokhtari Tahmineh,Pourabdollah Mihan,Nadji Seyed Alireza,Ragerdi Kashani Iraj
Background:Melatonin as an antioxidant agent can have an effective role in lung development. In this study, the effect of melatonin administration on lung injury in the neonate mice was assessed. Materials and Methods:Lung injury was induced by two injections of 15 mg/kg methylazoxymethanol (MAM) on gestational day 15 (E15). Pregnant BALB/c mice were randomly divided into five groups: Control (CO), Melatonin (MEL), Luzindole (Luz), MAM, and MAM+MEL. Melatonin and luzindole were intra-peritoneally injected at a dose of 10 mg/kg (from E15 until delivery). Histopathological changes including: hemorrhage, neutrophils infiltration and fibrosis in the neonate lung were studied by hematoxylin and eosin (H&E) and Masson's Trichrome staining. Alveolarization and alveolar wall thickness were measured. Results:In histological examination, hemorrhage, neutrophils infiltration and fibrosis were seen in the MAM and Luz groups; however, these injuries were attenuated in the MAM plus melatonin group. Significant reduction of alveolarization was recorded in the MAM and Luz groups compared to the control group, while the alveolar wall thickness was significantly increased in these groups compared to control group. Conclusion:Administration of exogenous melatonin in pregnant mice could have a protective effect on the pulmonary development of neonates and could decrease lung injury in neonate mice.
TLR2-Melatonin Feedback Loop Regulates the Activation of NLRP3 Inflammasome in Murine Allergic Airway Inflammation.
Wu Hui-Mei,Zhao Cui-Cui,Xie Qiu-Meng,Xu Juan,Fei Guang-He
Frontiers in immunology
Toll-like receptor 2 (TLR2) is suggested to initiate the activation of NLRP3 inflammasome, and considered to be involved in asthma. The findings that melatonin modulates TLRs-mediated immune responses, together with the suppressing effect of TLRs on endogenous melatonin synthesis, support the possibility that a feedback loop exists between TLRs system and endogenous melatonin synthesis. To determine whether TLR2-melatonin feedback loop exists in allergic airway disease and regulates NLRP3 inflammasome activity, wild-type (WT) and TLR2 mice were challenged with OVA to establish allergic airway disease model. Following OVA challenge, WT mice exhibited increased-expression of TLR2, activation of NLRP3 inflammasome and marked airway inflammation, which were all effectively inhibited in the TLR2 mice, indicating that TLR2-NLRP3 mediated airway inflammation. Meanwhile, melatonin biosynthesis was reduced in OVA-challenged WT mice, while such reduction was notably rescued by TLR2 deficiency, suggesting that TLR2-NLRP3-mediated allergic airway inflammation was associated with decreased endogenous melatonin biosynthesis. Furthermore, addition of melatonin to OVA-challenged WT mice pronouncedly ameliorated airway inflammation, decreased TLR2 expression and NLRP3 inflammasome activation, further implying that melatonin in turn inhibited airway inflammation via suppressing TLR2-NLRP3 signal. Most interestingly, although melatonin receptor antagonist luzindole significantly reduced the protein expressions of ASMT, AANAT and subsequent level of melatonin in OVA-challenged TLR2 mice, it exhibited null effect on leukocytes infiltration, Th2-cytokines production and NLRP3 activity. These results indicate that a TLR2-melatonin feedback loop regulates NLRP3 inflammasome activity in allergic airway inflammation, and melatonin may be a promising therapeutic medicine for airway inflammatory diseases such as asthma.