鞘氨醇-1-磷酸类似物抑制反复过敏原暴露后的气道重构
2012/02/29
背景：鞘氨醇-1-磷酸（S1P）是一种免疫调节性脂质介质，在淋巴细胞迁移中起到重要作用。研究发现，哮喘患者支气管肺泡灌洗液（BAL）中S1P水平增加，但其在哮喘中的作用尚不清楚。FTY720为一种合成的S1P类似物。研究显示它能抑制急性过敏原激发后的过敏性炎症和气道高反应性。然而，FTY720对反复过敏原暴露后气道重构的影响尚不清楚。
方法：采用卵清蛋白（OVA）对大鼠进行处理，其后在14、19和24天对其进行激发试验。每次激发试验之前1 h，采用FTY720或安慰剂（PBS）进行处理。最后一次激发试验48 h后，收集BAL进行分析，并进行定量组织分析。
结果：FTY720能抑制OVA诱导的气道重构特征（血管平滑肌体积增加和支气管血管新生）出现，但对二级淋巴器官的淋巴细胞数无影响。此外，在OVA激发的大鼠，粘附于气道平滑肌的CD3+细胞数显著增加，但FTY720能显著降低CD3+细胞数。OVA激发大鼠在FTY720处理后，支气管相关淋巴组织（BALT）有所增加。实时定量PCR检测显示，FTY720处理能抑制Th2相关转录因子表达。
结论：气道重构是严重哮喘的一个重要特征。我们结果显示，FTY720能抑制过敏原诱导的气道重构。因此，我们认为，FTY720可作为严重哮喘治疗的一种新药物。
方法：采用卵清蛋白（OVA）对大鼠进行处理，其后在14、19和24天对其进行激发试验。每次激发试验之前1 h，采用FTY720或安慰剂（PBS）进行处理。最后一次激发试验48 h后，收集BAL进行分析，并进行定量组织分析。
结果：FTY720能抑制OVA诱导的气道重构特征（血管平滑肌体积增加和支气管血管新生）出现，但对二级淋巴器官的淋巴细胞数无影响。此外，在OVA激发的大鼠，粘附于气道平滑肌的CD3+细胞数显著增加，但FTY720能显著降低CD3+细胞数。OVA激发大鼠在FTY720处理后，支气管相关淋巴组织（BALT）有所增加。实时定量PCR检测显示，FTY720处理能抑制Th2相关转录因子表达。
结论：气道重构是严重哮喘的一个重要特征。我们结果显示，FTY720能抑制过敏原诱导的气道重构。因此，我们认为，FTY720可作为严重哮喘治疗的一种新药物。
（刘国梁 审校）
Am J Physiol Lung Cell Mol Physiol. 2012 Jan 27. [Epub ahead of print]
Am J Physiol Lung Cell Mol Physiol. 2012 Jan 27. [Epub ahead of print]
Karmouty-Quintana H, Hassan M, Siddiqui S, Tsuchiya K, Risse PA, Xicota-Vila L, Marti-Solano M, Martin JG.
Source
1McGill University.
1McGill University.
Abstract
BACKGROUND: Sphingosine-1-phosphate (S1P) is an immunomodulatory lipid mediator that plays an important role in lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar lavage (BAL) fluid of asthmatics; however, its role in disease is not known. FTY720, a synthetic analogue of S1P, has been shown to abrogate allergic inflammation and airway hyperresponsiveness following acute allergen challenge. However, its effects on asthmatic airway remodeling induced by repeated allergen exposure are unknown.
METHODS: Ovalbumin (OVA) sensitized rats were challenged on days 14, 19 and 24 after sensitization. FTY720 or vehicle (PBS) therapy was administered 1 h prior to each challenge. BAL fluid and quantitative histological analysis were performed 48 h after the last challenge.
RESULTS: FTY720 inhibited OVA-induced features of airways remodeling including increased ASM mass and bronchial neo-vascularization, without affecting lymphocyte numbers in secondary lymphoid organs. Furthermore, CD3+ cells adjacent to airway smooth muscle bundles were increased in OVA-challenged rats but the increase was inhibited by FTY720. There was an expansion of bronchus-associated-lymphoid-tissue (BALT) following FTY720 treatment of OVA challenged animals. Real time quantitative PCR revealed that Th2-associated transcription factors were inhibited following FTY720 therapy.
CONCLUSIONS: Airways remodeling is a cardinal feature of severe asthma. These results demonstrate that allergen-driven airway remodeling can be inhibited by FTY720, offering potential new therapies for the treatment of severe asthma.
BACKGROUND: Sphingosine-1-phosphate (S1P) is an immunomodulatory lipid mediator that plays an important role in lymphocyte trafficking. Elevated levels of S1P are found in bronchoalveolar lavage (BAL) fluid of asthmatics; however, its role in disease is not known. FTY720, a synthetic analogue of S1P, has been shown to abrogate allergic inflammation and airway hyperresponsiveness following acute allergen challenge. However, its effects on asthmatic airway remodeling induced by repeated allergen exposure are unknown.
METHODS: Ovalbumin (OVA) sensitized rats were challenged on days 14, 19 and 24 after sensitization. FTY720 or vehicle (PBS) therapy was administered 1 h prior to each challenge. BAL fluid and quantitative histological analysis were performed 48 h after the last challenge.
RESULTS: FTY720 inhibited OVA-induced features of airways remodeling including increased ASM mass and bronchial neo-vascularization, without affecting lymphocyte numbers in secondary lymphoid organs. Furthermore, CD3+ cells adjacent to airway smooth muscle bundles were increased in OVA-challenged rats but the increase was inhibited by FTY720. There was an expansion of bronchus-associated-lymphoid-tissue (BALT) following FTY720 treatment of OVA challenged animals. Real time quantitative PCR revealed that Th2-associated transcription factors were inhibited following FTY720 therapy.
CONCLUSIONS: Airways remodeling is a cardinal feature of severe asthma. These results demonstrate that allergen-driven airway remodeling can be inhibited by FTY720, offering potential new therapies for the treatment of severe asthma.
Am J Physiol Lung Cell Mol Physiol. 2012 Jan 27. [Epub ahead of print]
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淋巴细胞计数全基因组关联研究联合基因表达数据分析揭示新的哮喘候选基因
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生物活性黄酮醇—漆黄素—通过负向调节NF-κB抑制过敏性气道炎症
