- 作者列表："Hoshino M","Akitsu K","Kubota K","Ohtawa J
BACKGROUND:House dust mite (HDM) sublingual immunotherapy (SLIT) has demonstrated efficacy in clinical trials of patients with asthma. Airway inflammation is a characteristics of respiratory allergy, but its relationship to SLIT remain unclear. OBJECTIVE:We evaluate the association between clinical outcomes with pulmonary function and biomarkers in before and after HDM SLIT (UMIN-Number 000022390). METHODS:One hundred twelve patients with asthma sensitized to HDM were randomized to add-on 6 standardized quality (SQ)-HDM SLIT to pharmacotherapy or pharmacotherapy alone for 48 weeks. At baseline and end of study, biomarkers, blood eosinophils, serum IgE, serum periostin, fractional exhaled nitric oxide (FeNO), and spirometry and clinical symptoms were measured. Association between biomarkers and an increase in FEV1 of 120 ml or greater were analyzed. RESULTS:SLIT demonstrated a significant reduction of serum periostin (P < 0.001), FeNO (P < 0.01), and increase in HDM specific IgE (P < 0.05), FEV1 (P < 0.001) and improvement of clinical symptom scores, when compared to pharmacotherapy. The change in FEV1 correlated with the changes in serum periostin (r = 0.696, P < 0.001) and the changes in FeNO (r = 0.682, P < 0.001). The independent predictor of improvement in airflow limitation were change in serum periostin (r2 = 0.753, P = 0.013) and FeNO (P = 0.038). Based on cutoff values derived by receiver operating characteristic analysis (periostin 30.9 ng/mL, FeNO 28.0 ppb), patients were distinguished responders from non-responders, but with no predictive value for blood eosinophils or total IgE. The proportion of patients with both high periostin and FeNO levels was significantly higher in responder than in non-responder (P = 0.026). CONCLUSIONS AND CLINICAL RELEVANCE:Adding HDM SLIT to pharmacotherapy resulted in reduced serum periostin and FeNO, and improved pulmonary function. Serum periostin and FeNO may be useful biomarkers for prediction of SLIT.
背景: 屋尘螨 (HDM) 舌下免疫疗法 (SLIT) 已在哮喘患者的临床试验中证明有效。气道炎症是呼吸道过敏的特征，但其与 SLIT 的关系仍不清楚。 目的: 我们评价 HDM SLIT (UMIN-Number 000022390) 前后临床结局与肺功能和生物标志物之间的相关性。 方法: 将 112 例 HDM 致敏的哮喘患者随机分为两组，分别加入 6 个标准化质量 (SQ)-HDM SLIT 进行药物治疗或单用药物治疗 48 周。在基线和研究结束时，测量生物标志物、血嗜酸性粒细胞、血清 IgE 、血清 periostin 、呼出气一氧化氮 (FeNO) 、肺活量测定和临床症状。分析了生物标志物与 FEV1 增加 120毫升或更大的相关性。 结果: SLIT 可显著降低血清骨膜蛋白 (P < 0.001) 、 FeNO (P < 0.01) 和 HDM 特异性 IgE (P <0.05)。与药物治疗相比，FEV1 (P < 0.001) 和临床症状评分的改善。FEV1 的变化与血清骨膜蛋白的变化 (r = 0.696，P <0.001) 和 FeNO 的变化 (r = 0.682，P <0.001) 相关。气流受限改善的独立预测因子是血清骨膜蛋白 (r2 = 0.753，P = 0.013) 和 FeNO (P = 0.038) 的变化。根据受试者工作特征分析得出的截断值 (periostin 30.9 ng/mL，FeNO 28.0 ppb)，将患者与非应答者区分开来,但对血嗜酸性粒细胞或总 IgE 无预测价值。应答者同时具有高骨膜蛋白和 FeNO 水平的患者比例显著高于无应答者 (P = 0.026)。 结论和临床相关性: 在药物治疗的基础上加用 HDM SLIT 可降低血清 periostin 和 FeNO，改善肺功能。血清骨膜蛋白和 FeNO 可能是预测 SLIT 的有用生物标志物。
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.