Mycophenolate mofetil and triptolide alleviating airway inflammation in asthmatic model mice partly by inhibiting bone marrow eosinophilopoiesis.
Mycophenolate mofetil and triptolide alleviating airway inflammation in asthmatic model mice partly by inhibiting bone marrow eosinophilopoiesis.
复制标题
DOI：
10.1016/j.intimp.2008.03.009
复制
发表时间：
2008-07
影响因子：
5.6
通讯作者：
Hui Mao;Xue Chen;Qun Yi;Suyun Li;Zeng-li Wang;Fu-yu Li
中科院分区：
文献类型：
--
作者：
Hui Mao;Xue Chen;Qun Yi;Suyun Li;Zeng-li Wang;Fu-yu Li
骨髓嗜酸性粒细胞生成在哮喘动物和患者的慢性气道炎症中起主要作用。某些平喘药物可能通过抑制骨髓嗜酸性粒细胞生成来减轻哮喘气道炎症。免疫抑制剂常用于糖皮质激素难治性哮喘患者，并已被证明是有效的。但免疫抑制剂对骨髓嗜酸性粒细胞生成的影响尚未见报道。本研究旨在探讨吗替麦考酚酯（MMF）和雷公藤内酯醇（TP）对骨髓嗜酸性粒细胞（EOS）生成的影响，并进一步探讨免疫抑制剂的抗哮喘作用机制。Balb/c小鼠经卵清蛋白（OVA）致敏、激发建立哮喘模型，分别给予无菌生理盐水、霉酚酸酯（MMF）和茶多酚（TP）灌胃，每日1次，共2周。通过组织学和ELISA检测气道炎症以及外周血和骨髓中的炎症介质IL-5和嗜酸性粒细胞趋化因子。采用免疫细胞化学结合原位杂交技术和Western blot检测骨髓中IL-5 R α mRNA阳性细胞数和IL-5 R α表达。用抗BrdU免疫细胞化学法检测骨髓新生嗜酸性粒细胞计数。我们发现，霉酚酸酯和TP减弱OVA诱导的支气管肺泡灌洗液（BALF）中嗜酸性粒细胞（EOS）的募集，外周血中IL-5和eotaxin的炎症介质表达，肺组织中表达eotaxin的炎症细胞和骨髓中新产生的EOS的数量。此外，霉酚酸酯减少了CD 34+细胞从骨髓向外周血的迁移，这与骨髓中嗜酸性粒细胞趋化因子表达降低和骨髓细胞上CCR 3表达降低有关。而霉酚酸酯或茶多酚均不能降低哮喘小鼠骨髓中CD 34 +IL-5 R α mRNA+细胞（EOS祖细胞）的数量和IL-5 R α的表达。这些结果表明，霉酚酸酯和TP减少骨髓嗜酸性粒细胞生成;这与T细胞产生的IL-5减少有关，这有助于减轻哮喘中的过敏性气道炎症。此外，霉酚酸酯通过降低骨髓中嗜酸性粒细胞趋化因子（eotaxin）的水平和骨髓细胞表面趋化因子受体（CCR）3的表达，抑制CD 34+细胞从骨髓向外周血的迁移。
The bone marrow eosinophilopoiesis makes a major contribution to the chronic airway inflammation in asthmatic animals and patients. Some anti-asthmatic medicines alleviated the asthmatic airway inflammation by inhibiting the bone marrow eosinophilopoiesis. Immunosuppressive agents have been commonly used in patients with glucocorticoid refractory asthma and have been proved to be effective. However, the research on the effect of the immunosuppressive agents on the bone marrow eosinophilopoiesis has seldom been reported. The purpose of the study was to explore the effect of mycophenolate mofetil (MMF) and triptolide (TP) on the bone marrow eosinophilopoiesis and to further investigate the mechanisms of the immunosuppressive agents involved in the anti-asthmatic effect. Balb/c mice were sensitized and challenged by OVA to establish the asthmatic model, and respectively administered orally with sterile saline, MMF, and TP once daily for 2 weeks. Airway inflammation, and inflammatory mediators IL-5 and eotaxin in the peripheral blood and bone marrow were measured by histology and ELISA. Immunocytochemistry combined with in situ hybridization technique and Western blot analysis was performed to estimate the amount of CD34+IL-5Rα mRNA+cells and IL-5Rα expression in the bone marrow. The count of new produced eosinophils in the bone marrow was detected by anti-BrdU immunocytochemistry. We found that MMF and TP attenuated OVA-induced eosinophil (EOS) recruitment in bronchoalveolar lavage fluid (BALF), inflammatory mediator expression of IL-5 and eotaxin in the peripheral blood, inflammatory cells expressing eotaxin in the lung tissues and the number of new produced EOS in the bone marrow. Also, MMF abated the migration of CD34+cells from the bone marrow to the peripheral blood, which was associated with a decreased eotaxin expression in the bone marrow and a decreased CCR3 expression on bone marrow cells. While, MMF or TP failed to decrease the amount of CD34+IL-5Rα mRNA+cells (EOS progenitors), and IL-5Rα expression in the bone marrow of asthmatic model mice. These results demonstrated that MMF and TP reduce the eosinophilopoiesis of the bone marrow; this is associated with a decrease of IL-5 produced by T cells, which contribute to alleviate the allergic airway inflammation in asthma. In addition, MMF decreased the CD34+cells migration from the bone marrow to the peripheral blood by the reduction of the level of eotaxin in the bone marrow and the expression of CCR3on the bone marrow cells.