Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice
Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice
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DOI：
10.1111/bph.14861
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发表时间：
2019-11-06
影响因子：
7.3
通讯作者：
Roviezzo, Fiorentina
中科院分区：
文献类型：
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作者：
De Cunto, Giovanna;Brancaleone, Vincenzo;Roviezzo, Fiorentina
背景和目的鞘氨醇激酶/鞘氨醇-1-磷酸（S1 P）通路在呼吸系统疾病中对气道功能的调控起着重要作用。在这里，我们解决S1 P在轻度慢性阻塞性肺疾病（COPD）小鼠模型的贡献。实验方法将C57 BL/6 J小鼠暴露于室内空气或香烟烟雾长达11个月，并在不同时间点处死。已经进行了功能和分子研究。关键结果香烟烟雾引起整个肺实质的气肿性变化，并在支气管周围和支气管周围区域引起进行性胶原沉积。高低气道对胆碱能刺激和α-平滑肌肌动蛋白过度表达的反应性增加。同样，吸烟小鼠在S1 P激发后气道反应性和肺阻力增加。在吸烟小鼠的肺中检测到S1 P、Sph-K-2和S1 P受体（S1 P（2）和S1 P（3））的高表达。抑制鞘氨醇激酶可逆转吸烟小鼠气道中增加的胆碱能反应。结论和意义S1 P信号上调遵循吸烟小鼠的疾病进展，并参与气道高反应性的发展。我们的研究确定了S1 P抑制剂在管理与哮喘和COPD吸烟者肺气肿相关的气道高反应性方面的治疗潜力。
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 alpha-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-K-2, and S1P receptors (S1P(2) and S1P(3)) 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.