Role of ventilatory control instability in children with sleep-disordered breathing.
- 作者列表："Siriwardhana LS","Weichard A","Nixon GM","Davey MJ","Walter LM","Edwards BA","Horne RSC
BACKGROUND AND OBJECTIVE:The contribution of non-anatomical factors, such as ventilatory control instability (i.e. LG), to the pathogenesis of obstructive SDB in children is unclear. Therefore, we aimed to identify the relationship between LG and severity of SDB, demographic, anthropometric and anatomical characteristics in a clinically representative cohort of children. METHODS:Children (aged 3-18 years) with various severities of SDB (n = 110) and non-snoring controls (n = 36) were studied. Children were grouped according to their OAHI. Anthropometric and upper airway anatomical characteristics were measured. Spontaneous sighs were identified on polysomnography and LG, a measure of the sensitivity of the negative feedback loop that controls ventilation, was estimated by fitting a mathematical model of ventilatory control to the post-sigh ventilatory pattern. RESULTS:There was no difference in LG between controls and any of the SDB severity groups. However, LG was significantly lower in children with larger tonsils (tonsil grade 4) compared with children with smaller tonsils (tonsil grade 1) (median LG (range): 0.25 (0.20-0.42) vs 0.32 (0.25-0.44); P = 0.009) and in children with a modified Mallampati score of class III/IV compared with class I (0.28 (0.24-0.33) vs 0.37 (0.27-0.44); P = 0.009). CONCLUSION:A direct relationship was not found between the severity of paediatric SDB and LG. However, an altered ventilatory control sensitivity may contribute to SDB in a subgroup of children depending on their degree of anatomical compromise of the airway.
背景与目的: 非解剖因素的贡献，如通气控制不稳定 (LG)，儿童阻塞性 SDB 的发病机制尚不清楚。因此，我们旨在确定临床代表性儿童队列中 LG 与 SDB 严重程度、人口统计学、人体测量和解剖学特征之间的关系。 方法: 对 3 ~ 18 岁不同程度 SDB 儿童 (n = 110) 和非鼾症对照组 (n = 36) 进行研究。根据 OAHI 对儿童进行分组。测量人体测量和上气道解剖特征。在多导睡眠图和 LG 上发现了自发叹气，LG 是控制通气的负反馈回路敏感性的指标,通过拟合呼吸控制的数学模型来估计叹气后通气模式。 结果: 对照组和任何 SDB 严重程度组之间的 LG 没有差异。然而，与扁桃体较小 (扁桃体 1 级) 的儿童相比，扁桃体较大 (扁桃体 4 级) 的儿童 LG 显著较低 (LG (范围) 中位数: 0.25 (0.20-0.42) vs 0.32 (0.25-0.44); P = 0.009)与 I 级相比，改良 Mallampati 评分为 III/IV 级的儿童 (0.28 (0.24-0.33) vs 0.37 (0.27-0.44); P = 0.009)。 结论: 儿童 SDB 的严重程度与 LG 之间未发现直接关系。然而，通气控制敏感性的改变可能有助于儿童亚组的 SDB，这取决于他们对气道解剖妥协的程度。
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.