Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy.
Department of Science, University of Basilicata, Potenza, Italy.
Br J Pharmacol. 2020 Jan;177(2):267-281. doi: 10.1111/bph.14861. Epub 2019 Nov 6.
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).
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.
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-K , and S1P receptors (S1P and S1P ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice.
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.
在呼吸系统疾病中，已经证明鞘氨醇激酶/鞘氨醇-1-磷酸（S1P）途径在气道功能的控制中起着关键作用。在这里，我们研究了 S1P 在轻度慢性阻塞性肺疾病（COPD）小鼠模型中的作用。
C57BL/6J 小鼠暴露于空气或香烟烟雾中长达 11 个月，并在不同时间点处死。进行了功能和分子研究。
香烟烟雾导致整个肺实质出现气肿性改变，并伴有细支气管周围和细支气管周围区域的胶原沉积逐渐增加。高气道和低气道对胆碱能刺激和α-平滑肌肌动蛋白过表达的反应性增加。同样，吸烟小鼠在 S1P 挑战后气道反应性和肺阻力增加。吸烟小鼠的肺中检测到 S1P、Sph-K 和 S1P 受体（S1P 和 S1P ）的高表达。鞘氨醇激酶抑制可逆转吸烟小鼠气道中胆碱能反应的增加。
S1P 信号通路的上调伴随着吸烟小鼠疾病的进展，并参与了气道高反应性的发展。我们的研究为 S1P 抑制剂在管理与吸烟者肺气肿相关的气道高反应性方面提供了治疗潜力，这些吸烟者既有哮喘又有 COPD。
