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Ciprofibrate attenuates airway remodeling in cigarette smoke-exposed rats.

环丙贝特减轻香烟烟雾暴露大鼠的气道重塑。

  • 影响因子:1.48
  • DOI:10.1016/j.resp.2019.103290
  • 作者列表:"Ke Q","Yang L","Cui Q","Diao W","Zhang Y","Xu M","He B
  • 发表时间:2020-01-01
Abstract

:Airway remodeling is a key pathological lesion in chronic obstructive pulmonary disease (COPD), and it leads to poorly reversible airway obstruction. Current pharmacological interventions are ineffective at controlling airway remodeling. To address this issue, we queried the Connectivity Map (cMap) database to screen for drug candidates that had the potential to dilate the bronchus and inhibit airway smooth muscle (ASM) proliferation. We identified ciprofibrate as a drug candidate. Ciprofibrate inhibited cigarette smoke extract-induced rat ASM cell contraction and proliferation in vitro. We exposed Sprague-Dawley (SD) rats to clean air or cigarette smoke (CS) and treated the rats with ciprofibrate. Ciprofibrate improved pulmonary function, inhibited airway hypercontraction, and ameliorated morphological small airway remodeling, including airway smooth muscle proliferation, in CS-exposed rats. Ciprofibrate also significantly reduced IL-1β, IL-12p70, IL-17A and IL-18 expression, which are related to airway remodeling, in the sera of CS-exposed rats. These findings indicate that ciprofibrate could attenuate airway remodeling in CS-exposed rats.

摘要

气道重塑是慢性阻塞性肺疾病 (COPD) 的关键病理病变,并导致可逆性气道阻塞。目前的药物干预对控制气道重塑无效。为了解决这个问题,我们查询了连接图 (cMap) 数据库,以筛选有可能扩张支气管和抑制气道平滑肌 (ASM) 增殖的候选药物。我们确定环丙贝特为候选药物。环丙贝特在体外抑制香烟烟雾提取物诱导的大鼠 ASM 细胞收缩和增殖。我们将 Sprague-Dawley (SD) 大鼠暴露于清洁空气或香烟烟雾 (CS) 中,并用环丙贝特对大鼠进行处理。环丙贝特改善 CS 暴露大鼠的肺功能,抑制气道过度收缩,改善形态学小气道重塑,包括气道平滑肌增殖。环丙贝特还显著降低 CS 暴露大鼠血清中与气道重塑相关的 il-1 β 、 IL-12p70 、 IL-17A 和 IL-18 的表达。这些发现表明环丙贝特可以减轻 CS 暴露大鼠的气道重塑。

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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.

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影响因子:3.94
发表时间:2020-01-15
DOI:10.1016/j.taap.2019.114847
作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

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关键词: 暂无
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影响因子:4.04
发表时间:2020-01-10
DOI:10.1042/BST20191010
作者列表:["Zaragosi LE","Deprez M","Barbry P"]

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