Reduced allergic lung inflammation and airway responsiveness in mice lacking the cytoskeletal protein gelsolin.
Reduced allergic lung inflammation and airway responsiveness in mice lacking the cytoskeletal protein gelsolin.
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减少缺乏细胞骨架蛋白凝溶胶蛋白的小鼠的过敏性肺部炎症和气道反应性。
DOI：
10.1152/ajplung.00065.2020
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Emala,CharlesW
中科院分区：
文献类型：
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作者：
Mikami,Maya;Yocum,GeneT;Heller,NicolaM;Emala,CharlesW
与慢性气道炎症相关的气道平滑肌高反应性导致哮喘的典型症状，包括支气管收缩和喘息。哮喘的严重程度与气道炎症相关;因此，减少气道炎症是一个重要的治疗目标。凝溶胶蛋白是一种肌动蛋白加帽和切断蛋白，已报道其参与炎症反应的调节。使用基因缺乏凝溶胶蛋白的小鼠，我们评估了凝溶胶蛋白在建立屋尘螨（HDM）抗原诱导的过敏性肺部炎症中的作用。发现凝溶胶蛋白的遗传缺失对HDM致敏具有保护作用，导致肺炎症、炎性细胞因子和支气管肺泡灌洗液（BAL）中的Muc 5AC蛋白减少。在野生型小鼠中，HDM致敏后BAL中嗜酸性粒细胞、淋巴细胞和间质巨噬细胞的数量增加，但在无凝溶胶蛋白小鼠中减少。观察到的炎症减弱可能部分是由于免疫细胞的迁移延迟，因为尽管有相似量的趋化因子嗜酸性粒细胞活化趋化因子，但与对照组相比，来自凝溶胶蛋白缺失小鼠的巴尔斯中的嗜酸性粒细胞减少。脾T细胞表现出类似的增殖率，但离体肺泡巨噬细胞迁移延迟凝溶胶蛋白基因敲除小鼠。在体内，与HDM治疗的野生型小鼠相比，无凝溶胶蛋白小鼠中HDM致敏后肺部炎症的减少与吸入乙酰甲胆碱的气道阻力显著降低相关。我们的研究结果表明，在调节过敏性肺部炎症的选择性炎症细胞类型中，调节凝溶胶蛋白的表达或功能可能是哮喘的一种治疗方法。
Airway smooth muscle hyperresponsiveness associated with chronic airway inflammation leads to the typical symptoms of asthma including bronchoconstriction and wheezing. Asthma severity is associated with airway inflammation; therefore, reducing airway inflammation is an important therapeutic target. Gelsolin is an actin capping and severing protein that has been reported to be involved in modulation of the inflammatory response. Using mice genetically lacking gelsolin, we evaluated the role of gelsolin in the establishment of house dust mite (HDM) antigen-induced allergic lung inflammation. The genetic absence of gelsolin was found to be protective against HDM sensitization, resulting in reduced lung inflammation, inflammatory cytokines, and Muc5AC protein in bronchoalveolar lavage (BAL) fluid. The number of eosinophils, lymphocytes, and interstitial macrophages in the BAL were increased after HDM sensitization in wild-type mice but were attenuated in gelsolin-null mice. The observed attenuation of inflammation may be partly due to delayed migration of immune cells, because the reduced eosinophils in the BALs from gelsolin-null mice compared with controls occurred despite similar amounts of the chemoattractant eotaxin. Splenic T cells demonstrated similar proliferation rates, but ex vivo alveolar macrophage migration was delayed in gelsolin-null mice. In vivo, the reduced lung inflammation after HDM sensitization in gelsolin-null mice was associated with significantly diminished airway resistance to inhaled methacholine compared with HDM-treated wild-type mice. Our results suggest that modulation of gelsolin expression or function in selective inflammatory cell types that modulate allergic lung inflammation could be a therapeutic approach for asthma.