Methane attenuates lung ischemia-reperfusion injury via regulating PI3K-AKT-NFκB signaling pathway.

甲烷通过调节 pi3k-akt-nf κ b 信号通路减轻肺缺血再灌注损伤。

  • 影响因子:1.92
  • DOI:10.1080/10799893.2020.1727925
  • 作者列表:"Wang F","Wang F","Li F","Wang D","Li H","He X","Zhang J
  • 发表时间:2020-02-21

:Objective: This study aims to investigate the protective effects and possible mechanism of methane-rich saline (MS) on lung ischemia-reperfusion injury (LIRI) in rats.Methods: MS (2 ml/kg and 20 ml/kg) was injected intraperitoneally in rats after LIRI. Lung injury was assayed by Hematoxylin-eosin (HE) staining and wet-to-dry weight (W/D). The cells in the bronchoalveolar lavage fluid (BALF) and blood were counted. Oxidative stress was examined by the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-10 (IL-10) were determined by ELISA. Lung tissue apoptosis was detected by TUNEL staining and western blotting of Bcl-2, Bax, and caspase-3. The expressions of IкBα, p38, PI3K, AKT, and NF-κB were analyzed with Western blotting.Results: MS effectively decreased the lung W/D ratio as well as the lung pathological damage and reduced the localized infiltration of inflammatory cells. Methane suppressed the expression of the PI3K-AKT-NFκB signaling pathway during the lung IR injury, which inhibited the activation of NF-kB and decreased the level of inflammatory cytokines, such as TNF-α, IL-1β, and IL-10. Moreover, we found that MS treatment relieved reactive oxygen species (ROS) damage by downregulating MDA and upregulating SOD. MS treatment also regulated apoptosis-related proteins, such as Bcl-2, Bax, and caspase-3.Conclusions: MS could repair LIRI and reduce the release of oxidative stress, inflammatory cytokines, and cell apoptosis via the PI3K-AKT-NFκB signaling pathway, which may provide a novel and promising strategy for the treatment of LIRI.


目的: 探讨富含甲烷的生理盐水 (MS) 对大鼠肺缺血再灌注损伤 (LIRI) 的保护作用及可能机制。方法: LIRI 后大鼠腹腔注射 MS (2 ml/kg 和 20 ml/kg)。采用苏木精-伊红 (HE) 染色和湿重-干重 (W/D) 测定肺损伤。计数支气管肺泡灌洗液 (BALF) 和血液中的细胞。通过丙二醛 (MDA) 和超氧化物歧化酶 (SOD) 水平检测氧化应激。采用 ELISA 法检测炎症因子肿瘤坏死因子-α (TNF-α) 、白细胞介素-1 β (il-1 β) 和 白介素-10 (IL-10)。采用 TUNEL 染色和 western blotting 法检测肺组织细胞凋亡 Bcl-2 、 Bax 和半胱天冬酶-3。Western blotting 分析 i к b α 、 p38 、 PI3K 、 AKT 和 NF-κ b 的表达。结果: MS 能有效降低肺 W/D 比值,减轻肺组织病理损伤,减少炎性细胞浸润。甲烷抑制肺 IR 损伤过程中 pi3k-akt-nf-κ b 信号通路的表达,从而抑制 NF-kB 的活化,降低 TNF-α 、 il-1 β 、还有 IL-10.此外,我们发现 MS 治疗通过下调 MDA 和上调 SOD 来缓解活性氧 (ROS) 损伤。MS 治疗还调节凋亡相关蛋白,如 Bcl-2 、 Bax 和 半胱天冬酶-3。结论: MS 可以修复 LIRI,减少氧化应激、炎性细胞因子、通过 pi3k-akt-nf κ b 信号通路进行细胞凋亡,这可能为治疗 LIRI 提供了一种新的、有前途的策略。



作者列表:["De Cunto G","Brancaleone V","Riemma MA","Cerqua I","Vellecco V","Spaziano G","Cavarra E","Bartalesi B","D'Agostino B","Lungarella G","Cirino G","Lucattelli M","Roviezzo F"]

METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

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作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

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作者列表:["Zaragosi LE","Deprez M","Barbry P"]

METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.

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