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 to 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.

中文翻译：

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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。

与慢性气道炎症相关的气道平滑肌高反应性导致典型的哮喘症状，包括支气管收缩和喘息。哮喘的严重程度与气道炎症有关；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，据报道它参与炎症反应的调节。使用遗传上缺乏凝溶胶蛋白的小鼠，我们评估了凝溶胶蛋白在屋尘螨 (HDM) 抗原诱导的过敏性肺部炎症的建立中的作用。发现凝溶胶蛋白的基因缺失可以防止 HDM 致敏，从而减少支气管肺泡灌洗 (BAL) 液中的肺部炎症、炎性细胞因子和 Muc5AC 蛋白。嗜酸性粒细胞数量，BAL 中的淋巴细胞和间质巨噬细胞在野生型小鼠 HDM 致敏后增加，但在凝溶胶蛋白缺失小鼠中减弱。观察到的炎症减弱可能部分是由于免疫细胞的延迟迁移，因为与对照组相比，尽管趋化性嗜酸性粒细胞趋化因子的量相似，但凝溶胶蛋白缺失小鼠的 BAL 中嗜酸性粒细胞减少。脾脏 T 细胞表现出相似的增殖率，但离体肺泡巨噬细胞迁移在凝溶胶蛋白缺失小鼠中延迟。在体内，与 HDM 处理的野生型小鼠相比，凝溶胶蛋白缺失小鼠 HDM 致敏后肺部炎症减少与吸入乙酰甲胆碱的气道阻力显着降低有关。