- 作者列表："Liu S","Chen D","Luo Q","Gong Y","Yin Y","Cao J
:Invasive pulmonary aspergillosis is a life-threatening disease, particularly in immunocompromised patients despite currently available therapy. Interleukin-27 (IL-27) is an important regulatory cytokine in infection and immunity. However, its role in the pathogenesis of invasive pulmonary aspergillosis remains unknown. Here we found that A. fumigatus pulmonary infection induced an elevated production of IL-27 in the lung. As compared to wild-type (WT) mice, IL-27 receptor (IL-27R)-deficient mice developed less severe infection when challenged with A. fumigatus conidia, as evidenced by the decreased fungal colonization and pathology of lungs and the increased survival. IL-27R deficiency led to significantly higher production of IFN-γ in the lung after A. fumigatus infection, and the increased resistance to invasive pulmonary A.fumigatus infection in IL-27R-deficient mice was ablated by neutralizing IFN-γ. Importantly, neutralization of IL-27 could protect WT mice against invasive pulmonary A.fumigatus infection. Our data therefore suggests an important role of IL-27 in impairing anti-A.fumigatus host immunity, which may have translational implications in treating clinical cases of invasive pulmonary aspergillosis.
: 侵袭性肺曲霉病是一种危及生命的疾病，特别是在免疫功能低下的患者中，尽管目前有可用的治疗方法。Interleukin-27 (IL-27) 是感染和免疫中重要的调节细胞因子。然而，其在侵袭性肺曲霉病发病机制中的作用仍不清楚。在这里，我们发现烟曲霉肺部感染诱导肺内 IL-27 的产生增加。与野生型 (WT) 小鼠相比，IL-27 受体 (IL-27R) 缺陷小鼠在 A 攻击时感染程度较轻。烟曲霉分生孢子，表现为肺部真菌定植和病理减少，存活率增加。IL-27R 缺乏导致 IFN-γ 在 A. 烟曲霉感染，对侵袭性肺 A 的抵抗力增加。通过中和 IFN-γ 的方法，对 IL-27R-deficient 小鼠的烟曲霉感染进行消融。重要的是，中和 IL-27 可以保护 WT 小鼠免受侵袭性肺部烟曲霉感染。因此，我们的数据表明 IL-27 在损害宿主免疫 anti-A.fumigatus 重要作用，这可能在治疗侵袭性肺曲霉病的临床病例中具有翻译意义。
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.