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Protective effect of MOTS-c on acute lung injury induced by lipopolysaccharide in mice.

MOTS-c 对脂多糖诱导小鼠急性肺损伤的保护作用

  • 影响因子:3.32
  • DOI:10.1016/j.intimp.2019.106174
  • 作者列表:"Xinqiang Y","Quan C","Yuanyuan J","Hanmei X
  • 发表时间:2020-01-10
Abstract

:MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA-c), a mitochondrial-derived 16-amino acid peptide, targets the methionine-folate cycle, increases 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels, and eventually activates AMP-activated protein kinase (AMPK). AMPK activation can attenuate neutrophil pro-inflammatory activity and attenuates lipoteichoic acid (LTA) and lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. However, to our knowledge, the role of MOTS-c in LPS-induced ALI remains unclear. Hence, we investigated the potential effectiveness and underlying mechanism of MOTS-c against LPS-induced ALI in mice. The intraperitoneal administration of MOTS-c (5 mg/kg, i.p., bid, 6 days) before intratracheal LPS instillation attenuated body weight loss and pulmonary edema, inhibited neutrophilic tissue infiltration in lung tissue, downregulated the expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) and intercellular cell adhesion molecule-1 (ICAM-1) in lung tissues, decreased the levels of TNF-α, IL-1β, and IL-6, and increased the expression of IL-10 and SOD in serum, lung tissue, and bronchoalvelolar lavage fluid (BALF). Moreover, MOTS-c treatment significantly promoted p-AMPKα and SIRT1 expression and suppressed LPS-induced ERK, JNK, p38, p65, and STAT3 activation in the mouse lung tissues. Collectively, these findings suggest that MOTS-c plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of MOTS-c are probably orchestrated by activating AMPK and SIRT1, inhibiting ERK, JNK, p65, and STAT3 signaling pathways. Thus, MOTS-c appears to be a novel and promising candidate for the treatment of ALI.

摘要

: MOTS-c (12 S rRNA-c 的线粒体开放阅读框架),一种线粒体衍生的 16 氨基酸肽,靶向甲硫氨酸-叶酸循环, 增加 5-氨基咪唑-4-甲酰胺核糖核苷酸 (AICAR) 水平,最终激活 AMP 活化蛋白激酶 (AMPK)。AMPK 激活可减弱中性粒细胞促炎活性,减弱脂磷壁酸 (LTA) 和脂多糖 (LPS) 诱导的小鼠急性肺损伤 (ALI)。然而,据我们所知,MOTS-c 在 LPS 诱导的 ALI 中的作用仍不清楚。因此,我们研究了 MOTS-c 对 LPS 诱导的小鼠 ALI 的潜在有效性和潜在机制。腹腔给药 MOTS-c (5 mg/kg,i。 p., bid,6 天) 前气管内滴入 LPS 可减轻体重下降和肺水肿,抑制肺组织中性粒细胞组织浸润,下调细胞因子诱导的中性粒细胞化学引诱物-1 (CINC-1) 的表达和肺组织细胞间粘附分子-1 (ICAM-1),降低血清、肺组织和支气管肺泡灌洗液 (BALF) 中 TNF-α 、 il-1 β 和 IL-6 的水平,增加 IL-10 、 SOD 的表达。此外,在小鼠肺组织中,MOTS-c 处理显著促进 p-ampk α 和 SIRT1 表达,抑制 LPS 诱导的 ERK 、 JNK 、 p38 、 p65 和 STAT3 活化。总的来说,这些发现表明 MOTS-c 在保护肺免受 LPS 诱导的 ALI 的炎症作用中发挥重要作用。MOTS-c 的作用可能是通过激活 AMPK 和 SIRT1,抑制 ERK 、 JNK 、 p65 和 STAT3 信号通路来编排的。因此,MOTS-c 似乎是治疗 ALI 的一种新颖而有前途的候选药物。

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影响因子:3.94
发表时间:2020-01-15
DOI:10.1016/j.taap.2019.114847
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.

关键词: 暂无
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影响因子:4.04
发表时间:2020-01-10
DOI:10.1042/BST20191010
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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