Dioscin alleviates lipopolysaccharide-induced acute lung injury through suppression of TLR4 signaling pathways.
薯蓣皂苷通过抑制 TLR4 信号通路减轻脂多糖诱导的急性肺损伤。
- 作者列表："Wang C","Li Q","Li T
:Aim:Acute lung injury (ALI) is a life-threatening inflammatory syndrome that lacks an effective therapy. Dioscin, a natural steroid saponin isolated from a variety of herbs, could serve as an anti-inflammatory agent, as suggested in previous reports. The purpose of this study was to explore the effects of dioscin on lipopolysaccharide (LPS)-induced ALI and validate the potential mechanisms.Materials and Methods:An ALI model was induced by intratracheal administration of LPS. Dioscin (20, 40, and 80 mg/kg) was administered intragastrically once daily for seven consecutive days prior to LPS challenge.Results:Our data revealed that dioscin significantly suppressed LPS-induced lung pathological changes, pulmonary capillary permeability, pulmonary edema, inflammatory cell infiltration, myeloperoxidase (MPO) activity, and cytokine production, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and keratinocyte chemoattractant (KC). Moreover, dioscin inhibited LPS-induced nuclear factor-kappaB (NF-κB) activation as well as Toll-like receptor 4 (TLR4) expression.Conclusions:In brief, the results indicated that dioscin alleviates LPS-induced ALI through suppression of TLR4 signaling pathways.
目的: 急性肺损伤 (ALI) 是一种危及生命的炎症综合征，目前尚缺乏有效的治疗方法。薯蓣皂苷是一种从多种草药中分离出来的天然甾体皂苷，可作为抗炎剂，如以前的报道所示。本研究的目的是探讨薯蓣皂苷对脂多糖 (LPS) 诱导的 ALI 的影响，并验证其潜在的机制。材料和方法: 采用气管内注射 LPS 诱导 ALI 模型。薯蓣皂苷 (20 、 40 和 80 mg/kg) 在 LPS 激发前连续 7 天每日一次灌胃给药。结果: 薯蓣皂苷能显著抑制 LPS 诱导的肺部病变、肺毛细血管通透性、肺水肿、炎性细胞浸润、髓过氧化物酶 (MPO) 活性和细胞因子的产生。包括肿瘤坏死因子(TNF)-α 、白细胞介素 (IL)-6 和角质形成细胞趋化因子 (KC)。此外，薯蓣皂苷能抑制 LPS 诱导的核因子-κ b (NF-κ b) 活化以及 Toll 样受体 4 (TLR4) 的表达。结论: 总之，结果表明薯蓣皂苷通过抑制 TLR4 信号通路减轻 LPS 诱导的 ALI。
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.
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.
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.