The effects of barium concentration levels on the pulmonary inflammatory response in a rat model of aspiration.
- 作者列表："Ueha R","Nativ-Zeltzer N","Sato T","Goto T","Yamauchi A","Belafsky PC","Yamasoba T
PURPOSE:Barium sulfate (Ba) suspension is the most widely used contrast agent for upper gastrointestinal and videofluoroscopic swallow studies (VFSS). The effect of Ba concentration on lung injury is uncertain. The aims of this study were to explore the effects of different barium concentrations on the respiratory organs and elucidate the underlying mechanisms of these effects in an established animal model of aspiration. METHODS:Animal model study. Eight-week-old male Sprague-Dawley rats were allocated into three groups (n = 12, each group). Two groups underwent tracheal instillation of low (30% w/v) and high (60% w/v) concentration Ba (low-Ba, high-Ba). A control group was instilled with saline. Half of the animals were euthanized on day 2 and the remaining half were euthanized on day 30. Histological and gene analyses were performed. RESULTS:Both low-Ba and high-Ba aspiration caused inflammatory cell infiltration in the lung at 2 days post aspiration with an increase in the expression of inflammatory cytokines. At 30 days post aspiration, small quantities of barium particles remained in the lung of the low-Ba group without any inflammatory reaction. Chronic inflammation was recognized in the high-Ba group up to 30 days post aspiration. CONCLUSION:A small amount of high concentration Ba (60% w/v) caused sustained inflammation in the rat lung at least 30 days after aspiration. Even with a small amount of low concentration Ba aspiration (30% w/v), Ba particles can remain in the lung over a month, causing sustained late effects.
目的: 硫酸钡 (Ba) 混悬液是上消化道和视频透视吞咽研究 (VFSS) 中应用最广泛的造影剂。Ba 浓度对肺损伤的影响还没有定论。本研究旨在探讨不同钡剂浓度对呼吸器官的影响，并在已建立的误吸动物模型中阐明这些影响的潜在机制。 方法: 动物模型研究。8 周龄雄性 Sprague-Dawley 大鼠分为三组 (n = 12，每组)。两组均行低 (30% w/v) 、高 (60% w/v) 浓度 Ba (低-Ba 、高-Ba) 气管滴注。对照组滴注生理盐水。一半的动物在第 2 天安乐死，其余一半在第 30 天安乐死。进行组织学和基因分析。 结果: 低 Ba 和高 Ba 吸入均可引起肺内炎性细胞浸润，且炎性细胞因子表达增加。抽吸后 30 天，低 Ba 组肺内仍有少量钡颗粒，无任何炎症反应。高 Ba 组在误吸后 30 天内发现慢性炎症。 结论: 少量高浓度 Ba (60% w/v) 在吸入后至少 30d 引起大鼠肺部持续炎症。即使少量低浓度 Ba 吸入 (30% w/v)，Ba 颗粒仍可在肺中停留一个月，引起持续的晚期效应。
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.