Hydrogen sulfide ameliorated lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/Akt/mTOR pathway in mice

Xu, Xiaolin; Li, Hao; Gong, Yuan; Zheng, Huiyu; Zhao, Deping

doi:10.1016/j.bbrc.2018.11.081

Cited by 35 publications

(22 citation statements)

References 21 publications

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“…5,6 Studies have shown that autophagy over-activation contributed to various ALI conditions. 7,25 In this study, we found that the expression of Beclin-1 and LC3I/II ratio observably increased after LPS treatment, both in vivo and in vitro, which further confirmed that autophagy was activated in LPS-induced ALI.…”

Section: Discussionsupporting

confidence: 76%

Hydrogen-rich saline ameliorated LPS-induced acute lung injury via autophagy inhibition through the ROS/AMPK/mTOR pathway in mice

Wang

Zhang

et al. 2019

Exp Biol Med (Maywood)

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Over-activation of autophagy due to increased levels of reactive oxygen species is a key mechanism of lipopolysaccharide-induced acute lung injury. Hydrogen-rich saline, an antioxidant, has been proved to be an effective agent for the prevention of acute lung injury, but the underlying mechanism remains unclear. Here, we investigated the mechanism through which hydrogen-rich saline prevents acute lung injury by focusing on autophagy regulation. The acute lung injury model was induced using lipopolysaccharide both in vivo and in vitro. The activation of autophagy was observed by detecting the expression of autophagy-related proteins using Western blotting. Lung histopathological changes, malondialdehyde content, wet/dry ratio, inflammatory cell count, protein content in bronchoalveolar lavage fluid, and cell viability were measured to evaluate the severity of acute lung injury. Intracellular reactive oxygen species levels were detected using dihydroethidium, which is a reactive oxygen species fluorescent probe. The results showed that the expression of Beclin-1 and microtubule-associated protein 1 light chain 3 II/I (LC3II/I ratio) was obviously increased after lipopolysaccharide administration. Pretreatment with hydrogen-rich saline markedly inhibited the expression of Beclin-1 and the LC3II/I ratio; ameliorated lung histopathological changes, malondialdehyde content and wet/dry ratio; and reduced protein content and infiltration of inflammatory cells in bronchoalveolar lavage fluid. These protective effects were also observed by pretreatment with autophagy inhibitor 3-methyladenine. Similar results were found in vitro. The production of reactive oxygen species and the activation of the AMPK/mTOR pathway were notably enhanced in MLE-12 cells after lipopolysaccharide treatment, and ameliorated by the hydrogen-rich medium. The activation of AMPK induced by lipopolysaccharide was also inhibited by pretreatment with N-acetyl-L-cysteine (a reactive oxygen species scavenger). In addition, the over-activation of autophagy was also suppressed by compound C (an AMPK inhibitor). In conclusion, hydrogen-rich saline alleviated lipopolysaccharide-induced acute lung injury by inhibiting excessive autophagy activation via the ROS/AMPK/mTOR pathway in mice. Hydrogen-rich saline may be a new therapeutic strategy for acute lung injury prevention and treatment in the future. Impact statement Acute lung injury (ALI), a common complication of many serious health issues, such as serious infection, burns, and shock, is one of the most common critical illnesses in clinical practice with a high mortality rate of 30–40%. There are still short of effective prevention and treatment measures. Evidence is growing that hydrogen-rich saline (HRS) may be an effective drug for the prevention and treatment of ALI. However, the mechanisms involved in have not been clearly understood. In this study, we investigated the underling mechanisms by focusing on autophagy regulation. The results showed that HRS ameliorated lipopolysaccharide-induced ALI in mice by inhibiting autophagy over-activation through ROS/AMPK/mTOR pathway. HRS may be a new therapeutic strategy for ALI prevention and treatment in the future.

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Section: Discussionsupporting

confidence: 76%

Hydrogen-rich saline ameliorated LPS-induced acute lung injury via autophagy inhibition through the ROS/AMPK/mTOR pathway in mice

Wang

Zhang

et al. 2019

Exp Biol Med (Maywood)

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“…it is important to identify regulatory molecules expressed in epithelial cells that are associated with macrophages. The Pi3K/akt pathway not only regulates various cellular functions, but also has roles in the signaling underlying epithelial barrier function during sepsis and ali/ardS (29,30). The present study identified activated Pi3K/akt signaling in Mle-12 cells co-cultured with M2 macrophages; however, the pathway was inhibited by lPS.…”

Section: Discussionmentioning

confidence: 45%

Tim‑3 regulates the ability of macrophages to counter lipopolysaccharide‑induced pulmonary epithelial barrier dysfunction via the PI3K/Akt pathway in epithelial cells

Zhang

2020

Mol Med Rep

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Pulmonary epithelial barrier dysfunction is a critical pathological component of lung injury, caused primarily by impaired epithelial cell migration. Moreover, macrophage-epithelial interactions in pulmonary alveoli may either protect or damage epithelial barrier function. To investigate the effects of different macrophage subtypes, M1 and M2, on lipopolysaccharide (lPS)-induced epithelial barrier dysfunction, M1 and M2 macrophages were used to treat lPS-injured musculus lung epithelial cells (Mle-12). Barrier function was evaluated by monitoring cell monolayer permeability, T-cell immunoglobulin mucin 3 (Tim-3) small interfering rna and anti-mouse Tim-3 antibody were used to knockdown or block endogenous Tim-3, to verify the role of the Tim-3 in macrophage-mediated barrier protection in lPS-injured Mle-12 cells. lY294002 was used to inhibit the activity of Pi3K to verify the role of the Pi3K/akt signaling pathway in the restoration of epithelial cell. The present results revealed that co-culture of lPS-treated epithelial Mle-12 cells with M1 macrophages decreased cell migration and promoted permeability, whereas co-culture with M2 macrophages caused the opposite effects. it was determined that blocking T-cell immunoglobulin mucin 3 (Tim-3) signaling in macrophages and Pi3K/akt signaling in epithelial cells eliminated the barrier protection supplied by M2 macrophages. Tim-3, which maintains macrophage M2 polarization, is a key component of the macrophage-mediated barrier-repair process, while M2 macrophages regulate Pi3K/akt signaling in epithelial cells, which in turn enhances pulmonary epithelial barrier function by restoring cell migration.

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“…These results suggested that CSE KO led to the decrease in H 2 S expression and activation of the RhoA/ROCK signal pathway, which may have aggravated the myocardial ischemic injury. H 2 S has protective effects against A/R injury in mice heart tissues by preventing the RhoA/ROCK signal pathway (20,26). TFR inhibition of the RhoA/ROCK signal pathway may be mediated by the CSE-H 2 S pathway.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of H2S‑mediated ROCK inhibition of total flavones of Rhododendra against myocardial ischemia injury

Jiao

Chen

et al. 2019

Exp Ther Med

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Our previous studies have indicated that pretreatment with total flavones of Rhododendra flower (TFR) may protect against myocardial ischemic injuries in rats and mice. The cystathionine γ-lyase/hydrogen sulfide (CSE/H2S) pathway have been associated with several cardiovascular diseases, but the effect of TFR on the Rho-associated protein kinase (ROCK) and CSE/H2S signaling pathways remains unknown. In the present study, the protective effects of TFR as a ROCK inhibitor in a mice model of myocardial infarction induced by isoproterenol (ISO) were investigated, and the hearts from the wild type and CSE knockout (KO) mice were examined. It was identified that the CSE KO mice exhibited decreased levels of ST segment elevation following anoxia/reoxygenation damage, increased LDH and CK-MB levels, aggravated pathological damage, and increased ROCK1, ROCK2 and MLC1 protein levels. In the CSE KO mice, there were no marked changes of the above experimental results between the TFR group and the model group. These results suggested that TFR-based inhibition of the RhoA/ROCK signal pathway may be mediated by the CSE-H2S signalling pathway and may be a novel therapeutic target for myocardial ischemia injury.

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Hydrogen sulfide ameliorated lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/Akt/mTOR pathway in mice

Cited by 35 publications

References 21 publications

Hydrogen-rich saline ameliorated LPS-induced acute lung injury via autophagy inhibition through the ROS/AMPK/mTOR pathway in mice

Hydrogen-rich saline ameliorated LPS-induced acute lung injury via autophagy inhibition through the ROS/AMPK/mTOR pathway in mice

Tim‑3 regulates the ability of macrophages to counter lipopolysaccharide‑induced pulmonary epithelial barrier dysfunction via the PI3K/Akt pathway in epithelial cells

Mechanism of H2S‑mediated ROCK inhibition of total flavones of Rhododendra against myocardial ischemia injury

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