Birt-Hogg-dub é 综合征自发性气胸的遗传危险因素。
- 作者列表："Sattler EC","Syunyaeva Z","Mansmann U","Steinlein OK
BACKGROUND:Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, spontaneous pneumothorax, fibrofolliculoma and renal cell cancer. Due to its rarity and clinical heterogeneity, much is still unknown regarding the course of the disease and individual risk assessment. Therefore, we studied non-environmental risk factors for pneumothorax in a large sample of BHDS patients. METHODS:Clinical data were available from 197 BHDS patients (male 103, female 94) belonging to 63 unrelated families. The FLCN coding region including adjacent intronic sequences was analysed by PCR and subsequent Sanger sequencing as well as MLPA. Statistical analyses were performed using adequate methods to account for familial clustering. RESULTS:Patients who had only a single spontaneous pneumothorax were significantly older at the time of occurrence than those with multiple ones (mean 38.93 versus 29.74 years, p-value 0.010). The risk for three or more pneumothoraces drastically increased after the second event. Significantly increased pneumothorax risks were found for mutations c.1300G>C (59%) and c.250-2A>G (77%), compared to FLCN hotspot mutation c.1285dup (37% risk) (p-value 0.02). CONCLUSIONS:We observed significant differences for the spontaneous pneumothorax risk regarding both age and gender in BHDS patients. Furthermore, two FLCN mutations were identified that are associated with significantly increased pneumothorax risk. Thus, formerly unknown individual predictors have been identified that provide improved risk stratification for BHDS patients.
背景: Birt-Hogg-dub é 综合征 (BHDS) 是一种以肺囊肿、自发性气胸、纤维滤泡瘤和肾细胞癌为特征的遗传性肿瘤综合征。由于其罕见性和临床异质性，关于病程和个体风险评估仍有许多未知。因此，我们在一个大样本的 BHDS 患者中研究了气胸的非环境危险因素。 方法: 临床资料来自 63 个无关家族的 197 例 BHDS 患者 (男性 103 例，女性 94 例)。通过 PCR 和随后的 Sanger 测序以及 MLPA 分析包括相邻内含子序列的 FLCN 编码区。使用适当的方法进行统计分析，以解释家族聚集性。 结果: 只有单个自发性气胸的患者在发生时明显比多个自发性气胸的患者年龄大 (平均 38.93 对 29.74 年，p 值 0.010)。第二次事件后，发生三次或更多次肺炎的风险急剧增加。与 FLCN 热点突变 c.1285dup (59% 风险) 相比，发现突变 c.1300G> C (77%) 和 c.250-2A> G (37%) 的气胸风险显著增加 (p 值 0.02)。 结论: 我们观察到 BHDS 患者的自发性气胸风险在年龄和性别方面存在显著差异。此外，确定了两个与气胸风险显著增加相关的 FLCN 突变。因此，以前未知的个体预测因子已经被确定，为 BHDS 患者提供了改善的风险分层。
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.