Department of Medicine, Basic Science Section, National Jewish Health, Denver, CO, United States of America.
Biological Resource Center, National Jewish Health, Denver, CO, United States of America.
Toxicol Appl Pharmacol. 2020 Oct 1;404:115186. doi: 10.1016/j.taap.2020.115186. Epub 2020 Aug 8.
Increased symptoms of asthma-like respiratory illnesses have been reported in soldiers returning from tours of duty in Afghanistan. Inhalation of desert particulate matter (PM) may contribute to this deployment-related lung disease (DRLD), but little is known about disease mechanisms. The IL-33 signaling pathway, including its receptor ST2, has been implicated in the pathogenesis of lung diseases including asthma, but its role in PM-mediated airway dysfunction has not been studied. The goal of this study was to investigate whether IL-33/ST2 signaling contributes to airway dysfunction in preclinical models of lung exposure to Afghanistan PM (APM). Wild-type (WT) and ST2 knockout (KO) mice on the BALB/C background were oropharyngeally instilled with a single dose of saline or 50 μg of APM in saline. Airway hyperresponsiveness (AHR) and inflammation were assessed after 24 h. In WT mice, a single APM exposure induced AHR and neutrophilic inflammation. Unlike the WT mice, ST2 KO mice that lack the receptor for IL-33 did not demonstrate AHR although airway neutrophilic inflammation was comparable to the WT mice. Oropharyngeal delivery of a soluble ST2 decoy receptor in APM-exposed WT mice significantly blocked AHR. Additional data in mouse tracheal epithelial cell and lung macrophage cultures demonstrated a role of APM-induced IL-33/ST2 signaling in suppression of regulator of G protein signaling 2 (RGS2), a gene known to protect against bronchoconstriction. We present for the first time that APM may increase AHR, one of the features of asthma, in part through the IL-33/ST2/RGS2 pathway.
有报道称，从阿富汗执行任务归来的士兵出现了类似哮喘的呼吸道疾病症状。吸入沙漠颗粒物质（PM）可能导致这种与部署相关的肺部疾病（DRLD），但对疾病机制知之甚少。IL-33 信号通路，包括其受体 ST2，已被牵连到包括哮喘在内的肺部疾病的发病机制中，但它在 PM 介导的气道功能障碍中的作用尚未得到研究。本研究的目的是研究 IL-33/ST2 信号通路是否参与了临床前暴露于阿富汗 PM（APM）的肺部模型中的气道功能障碍。BALB/C 背景下的野生型（WT）和 ST2 敲除（KO）小鼠通过口咽灌胃接受单次生理盐水或 50μg APM 生理盐水溶液。在 24 小时后评估气道高反应性（AHR）和炎症。在 WT 小鼠中，单次 APM 暴露会引起 AHR 和中性粒细胞炎症。与 WT 小鼠不同，缺乏 IL-33 受体的 ST2 KO 小鼠没有表现出 AHR，尽管气道中性粒细胞炎症与 WT 小鼠相当。在 APM 暴露的 WT 小鼠中，口咽给予可溶性 ST2 诱饵受体可显著阻断 AHR。在小鼠气管上皮细胞和肺巨噬细胞培养物中的额外数据表明，APM 诱导的 IL-33/ST2 信号通路在抑制 G 蛋白信号调节因子 2（RGS2）中起作用，RGS2 是一种已知可防止支气管痉挛的基因。我们首次提出，APM 可能通过 IL-33/ST2/RGS2 途径增加 AHR，这是哮喘的特征之一。
