Mikami Maya, Yocum Gene T, Heller Nicola M, Emala Charles W
Department of Anesthesiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
Am J Physiol Lung Cell Mol Physiol. 2020 Nov 1;319(5):L833-L842. doi: 10.1152/ajplung.00065.2020. Epub 2020 Sep 9.
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.
与慢性气道炎症相关的气道平滑肌高反应性会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，减轻气道炎症是一个重要的治疗靶点。凝溶胶蛋白是一种肌动蛋白封端和切割蛋白，据报道其参与炎症反应的调节。我们使用基因敲除凝溶胶蛋白的小鼠，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形成中的作用。结果发现，基因敲除凝溶胶蛋白可对HDM致敏起到保护作用，导致肺部炎症减轻、炎症细胞因子减少，支气管肺泡灌洗（BAL）液中的Muc5AC蛋白含量降低。HDM致敏后，野生型小鼠BAL中的嗜酸性粒细胞、淋巴细胞和间质巨噬细胞数量增加，但在凝溶胶蛋白基因敲除小鼠中则减少。观察到的炎症减轻可能部分归因于免疫细胞迁移延迟，因为尽管趋化因子嗜酸性粒细胞趋化因子的量相似，但与对照组相比，凝溶胶蛋白基因敲除小鼠BAL中的嗜酸性粒细胞减少。脾T细胞显示出相似的增殖率，但凝溶胶蛋白基因敲除小鼠的离体肺泡巨噬细胞迁移延迟。在体内，与HDM处理的野生型小鼠相比，凝溶胶蛋白基因敲除小鼠HDM致敏后肺部炎症减轻与吸入乙酰甲胆碱时气道阻力显著降低有关。我们的结果表明，调节凝溶胶蛋白在调节过敏性肺部炎症的选择性炎症细胞类型中的表达或功能可能是一种治疗哮喘的方法。
