选择性刺激平滑肌IL-4受体诱导小鼠气道高反应性
2011/06/17
摘要
研究发现，在人类哮喘和小鼠哮喘模型中，IL-4和IL-13生成增加，IL-4/IL-13R 活化Stat6 是导致小鼠哮喘病理生理学【包括气道高反应性(AHR)】的主要原因。然而，IL-4Rα诱导AHR的准确细胞机制仍不清楚。支气管平滑肌过度收缩被认为是人体哮喘中AHR的主要原因，但对于平滑肌在AHR中的作用尚未进行直接评价。此外，小鼠和人体的气道解剖结构存在差异，而且有观察发现，IL-13对气道上皮Stat6的选择性活化可诱导小鼠AHR，这些结果对IL-4R对小鼠哮喘模型中平滑肌的直接影响，以及这些动物模型与人体哮喘的相关性提出了质疑。在转基因小鼠中，平滑肌细胞是唯一可以表达IL-4Rα或无IL-4Rα表达的细胞类型。我们的结果显示，IL-4、IL-13和过敏原能直接活化平滑肌，但对于诱导AHR则不是必须的。体内研究发现，参与平滑肌迁移、增殖和收缩的5个基因能被IL-13所活化。这些研究结果显示，IL-4Rα能通过多种机制促进AHR，也为研究平滑肌相关哮喘治疗提供了模型。
（苏楠 审校）
J Exp Med. 2011 Apr 4. [Epub ahead of print]
Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice.
Perkins C, Yanase N, Smulian G, Gildea L, Orekov T, Potter C, Brombacher F, Aronow B, Wills-Karp M, Finkelman FD.
Department of Medicine and 2 Department of Research, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220.
Abstract
Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse versus human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and the relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient but not necessary to induce AHR. Five genes known to promote smooth muscle migration, proliferation, and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics.
J Exp Med. 2011 Apr 4. [Epub ahead of print]
研究发现，在人类哮喘和小鼠哮喘模型中，IL-4和IL-13生成增加，IL-4/IL-13R 活化Stat6 是导致小鼠哮喘病理生理学【包括气道高反应性(AHR)】的主要原因。然而，IL-4Rα诱导AHR的准确细胞机制仍不清楚。支气管平滑肌过度收缩被认为是人体哮喘中AHR的主要原因，但对于平滑肌在AHR中的作用尚未进行直接评价。此外，小鼠和人体的气道解剖结构存在差异，而且有观察发现，IL-13对气道上皮Stat6的选择性活化可诱导小鼠AHR，这些结果对IL-4R对小鼠哮喘模型中平滑肌的直接影响，以及这些动物模型与人体哮喘的相关性提出了质疑。在转基因小鼠中，平滑肌细胞是唯一可以表达IL-4Rα或无IL-4Rα表达的细胞类型。我们的结果显示，IL-4、IL-13和过敏原能直接活化平滑肌，但对于诱导AHR则不是必须的。体内研究发现，参与平滑肌迁移、增殖和收缩的5个基因能被IL-13所活化。这些研究结果显示，IL-4Rα能通过多种机制促进AHR，也为研究平滑肌相关哮喘治疗提供了模型。
（苏楠 审校）
J Exp Med. 2011 Apr 4. [Epub ahead of print]
Selective stimulation of IL-4 receptor on smooth muscle induces airway hyperresponsiveness in mice.
Perkins C, Yanase N, Smulian G, Gildea L, Orekov T, Potter C, Brombacher F, Aronow B, Wills-Karp M, Finkelman FD.
Department of Medicine and 2 Department of Research, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220.
Abstract
Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models, and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse versus human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and the relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient but not necessary to induce AHR. Five genes known to promote smooth muscle migration, proliferation, and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics.
J Exp Med. 2011 Apr 4. [Epub ahead of print]
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哮喘患者和健康对照者外周和中央气道成纤维细胞的白三烯受体表达呈现差异
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哮喘患者气道中的成纤维细胞表现为浸润表型
