Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model
Inhalation of sphingosine kinase inhibitor attenuates airway inflammation in asthmatic mouse model
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DOI：
10.1152/ajplung.00445.2007
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发表时间：
2008-06-01
影响因子：
4.9
通讯作者：
Nakamura, Shun-ichi
中科院分区：
文献类型：
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作者：
Nishiuma, Teruaki;Nishimura, Yoshihiro;Nakamura, Shun-ichi
鞘氨醇激酶(SPHK)产生的1-磷酸鞘氨醇(S1P)与急性免疫反应密切相关，但SPHK/S1P信号在哮喘发病机制中的作用机制尚不清楚。在这项研究中，我们假设抑制SPHK可以改善卵蛋白(OVA)攻击的小鼠肺的炎症。对6~8周龄C57BL/6J小鼠进行致敏处理，连续暴露3天。24小时后取小鼠肺和支气管肺泡灌洗液(BAL)进行分析。两种不同的SPHK抑制剂N，N-二甲基鞘氨醇(DMS)或SPHK抑制剂[SK-I；2-(p-羟基苯基)-4-(对氯苯基)噻唑]雾化30min后吸入OVA。吸入卵子后，S1P释放到BAL液中，SPHK1在支气管上皮壁和炎症区高表达。吸入DMS或SK-I可使BAL液中S1P含量降至基础水平，并伴有嗜酸性粒细胞浸润减少和过氧化物酶活性降低。吸入DMS引起的抑制程度高于SK-I。与Th2细胞因子的释放类似，DMS可显著抑制OVA吸入诱导的嗜酸性粒细胞趋化因子表达的增加，无论是在BAL液的蛋白水平还是在肺组织匀浆的mRNA水平上都是如此。此外，SPHK抑制剂还能改善吸入性乙酰胆碱的高反应性和杯状细胞增生。提示SPHK的抑制作用可影响抗原激发的小鼠急性嗜酸性炎症，靶向SPHK可能为治疗哮喘提供一种新的治疗手段。
Sphingosine 1-phosphate (S1P) produced by sphingosine kinase (SPHK) is implicated in acute immunoresponses, however, mechanisms of SPHK/S1P signaling in the pathogenesis of bronchial asthma are poorly understood. In this study, we hypothesized that SPHK inhibition could ameliorate lung inflammation in ovalbumin (OVA)-challenged mouse lungs. Six- to eight-week-old C57BL/6J mice were sensitized and exposed to OVA for 3 consecutive days. Twenty-four hours later, mice lungs and bronchoalveolar lavage (BAL) fluid were analyzed. For an inhibitory effect, either of the two different SPHK inhibitors, N,N-dimethylsphingosine (DMS) or SPHK inhibitor [SK-I; 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole], was nebulized for 30 min before OVA inhalation. OVA inhalation caused S1P release into BAL fluid and high expression of SPHK1 around bronchial epithelial walls and inflammatory areas. DMS or SK-I inhalation resulted in a decrease in S1P amounts in BAL fluid to basal levels, accompanied by decreased eosinophil infiltration and peroxidase activity. The extent of inhibition caused by DMS inhalation was higher than that caused by SK-I. Like T helper 2 (Th2) cytokine release, OVA inhalation-induced increase in eotaxin expression was significantly suppressed by DMS pretreatment both at protein level in BAL fluid and at mRNA level in lung homogenates. Moreover, bronchial hyperresponsiveness to inhaled methacholine and goblet cell hyperplasia were improved by SPHK inhibitors. These data suggest that the inhibition of SPHK affected acute eosinophilic inflammation induced in antigen-challenged mouse model and that targeting SPHK may provide a novel therapeutic tool to treat bronchial asthma.