Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation.
Induction of eosinophil apoptosis by the cyclin-dependent kinase inhibitor AT7519 promotes the resolution of eosinophil-dominant allergic inflammation.
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DOI：
10.1371/journal.pone.0025683
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Rossi AG
中科院分区：
文献类型：
--
作者：
Alessandri AL;Duffin R;Leitch AE;Lucas CD;Sheldrake TA;Dorward DA;Hirani N;Pinho V;de Sousa LP;Teixeira MM;Lyons JF;Haslett C;Rossi AG
嗜酸性粒细胞不仅可以保护身体免受寄生虫感染，还与哮喘、过敏性鼻炎和接触性皮炎等病理性炎症过敏性疾病有关。巨噬细胞清除凋亡的嗜酸性粒细胞是驱动嗜酸性粒细胞炎症消退的关键过程，并且在过敏性疾病中可能存在缺陷。然而，之前尚未证明通过使用药物有意诱导嗜酸性粒细胞凋亡来增强嗜酸性粒细胞炎症的消退。在这里，我们研究了一种新型细胞周期蛋白依赖性激酶抑制剂药物 AT7519 对人和小鼠嗜酸性粒细胞凋亡的影响，并检查它是否可以增强小鼠体内嗜酸性粒细胞主导炎症模型的消退。用 AT7519 处理来自健康供体血液的嗜酸性粒细胞，并通过形态学和流式细胞仪检测膜联蛋白-V/碘化丙啶染色来评估细胞凋亡。 AT7519 以浓度依赖性方式诱导嗜酸性粒细胞凋亡。使用已建立的卵清蛋白敏感的过敏性胸膜炎小鼠模型研究了 AT7519 在嗜酸性粒细胞为主的过敏性炎症中的治疗给药。卵清蛋白攻击后，在胸膜炎症高峰期全身施用 AT7519，在适当的时间点评估炎症细胞浸润、凋亡和巨噬细胞吞噬凋亡嗜酸性粒细胞的证据。 AT7519 的施用通过直接诱导嗜酸性粒细胞凋亡而显着增强过敏性胸膜炎的缓解，而不损害这些细胞的巨噬细胞清除。这种炎症消退的增强是半胱天冬酶依赖性的，因为广谱半胱天冬酶抑制剂 (z-vad-fmk) 治疗会降低 AT7519 的作用。我们的数据显示，AT7519 通过诱导 caspase 依赖性嗜酸性粒细胞凋亡和增强巨噬细胞对凋亡嗜酸性粒细胞的摄取，诱导人嗜酸性粒细胞凋亡并增强过敏性胸膜炎小鼠模型的消退。这些发现证明了细胞周期蛋白依赖性激酶抑制剂（例如 AT7519）作为治疗嗜酸性粒细胞显性过敏性疾病的潜在治疗剂的效用。
Eosinophils not only defend the body against parasitic infection but are also involved in pathological inflammatory allergic diseases such as asthma, allergic rhinitis and contact dermatitis. Clearance of apoptotic eosinophils by macrophages is a key process responsible for driving the resolution of eosinophilic inflammation and can be defective in allergic diseases. However, enhanced resolution of eosinophilic inflammation by deliberate induction of eosinophil apoptosis using pharmacological agents has not been previously demonstrated. Here we investigated the effect of a novel cyclin-dependent kinase inhibitor drug, AT7519, on human and mouse eosinophil apoptosis and examined whether it could enhance the resolution of a murine model of eosinophil-dominant inflammation in vivo. Eosinophils from blood of healthy donors were treated with AT7519 and apoptosis assessed morphologically and by flow-cytometric detection of annexin-V/propidium iodide staining. AT7519 induced eosinophil apoptosis in a concentration dependent manner. Therapeutic administration of AT7519 in eosinophil-dominant allergic inflammation was investigated using an established ovalbumin-sensitised mouse model of allergic pleurisy. Following ovalbumin challenge AT7519 was administered systemically at the peak of pleural inflammation and inflammatory cell infiltrate, apoptosis and evidence of macrophage phagocytosis of apoptotic eosinophils assessed at appropriate time points. Administration of AT7519 dramatically enhanced the resolution of allergic pleurisy via direct induction of eosinophil apoptosis without detriment to macrophage clearance of these cells. This enhanced resolution of inflammation was shown to be caspase-dependent as the effects of AT7519 were reduced by treatment with a broad spectrum caspase inhibitor (z-vad-fmk). Our data show that AT7519 induces human eosinophil apoptosis and enhances the resolution of a murine model of allergic pleurisy by inducing caspase-dependent eosinophil apoptosis and enhancing macrophage ingestion of apoptotic eosinophils. These findings demonstrate the utility of cyclin-dependent kinase inhibitors such as AT7519 as potential therapeutic agents for the treatment of eosinophil dominant allergic disorders.