Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis.
Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis.
复制标题
DOI：
10.1016/j.ajpath.2021.11.012
复制
发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
S. Teitz-Tennenbaum;Steven P. Viglianti;Ahmad Jomma;Q. Palone;H. Andrews;K. Selbmann;S. Lahiri
中科院分区：
文献类型：
--
作者：
S. Teitz-Tennenbaum;Steven P. Viglianti;Ahmad Jomma;Q. Palone;H. Andrews;K. Selbmann;S. Lahiri
部署到西南亚的士兵中发现了与部署相关的缩窄性毛细支气管炎(DRCB)的组织病理学证据。虽然对呼吸道上皮的吸入性损伤是可疑的，但对这种致残障碍的发病机制知之甚少。俱乐部细胞是暴露于各种空气传播毒素后对修复呼吸道上皮至关重要的局部祖细胞，先前使用可诱导转基因小鼠模型的研究报告称，持续10天的靶向俱乐部细胞损伤会导致缩窄性毛细支气管炎。为了进一步了解导致小气道纤维化的机制，采用小鼠模型显示，持续的俱乐部细胞损伤可引起急性体重减轻，导致局部促炎细胞因子的产生增加，并促进肺内大量髓系细胞亚群的聚集。过渡到慢性期的特征是氧化应激相关基因表达上调，转化生长因子-β激活增加，交替激活的巨噬细胞聚集，细支气管周胶原沉积增加。对比组织病理学分析表明，持续的俱乐部细胞损伤足以导致上皮化生、气道壁增厚、细支气管周浸润和管腔内巨噬细胞簇，这些细胞概括了DRCB中观察到的关键异常。耗尽小鼠肺泡巨噬细胞可降低转化生长因子-β的活性，改善缩窄性毛细支气管炎。总而言之，这些发现表明持续的俱乐部细胞损伤与DRCB的发展有关，并描绘了可能产生这种疾病的生物标记物和治疗靶点的途径。
Histopathologic evidence of deployment-related constrictive bronchiolitis (DRCB) has been identified in soldiers deployed to Southwest Asia. While inhalational injury to the airway epithelium is suspected, relatively little is known about the pathogenesis underlying this disabling disorder. Club cells are local progenitors critical for repairing the airway epithelium after exposure to various airborne toxins, and a prior study using an inducible transgenic murine model reported that 10 days of sustained targeted club cell injury causes constrictive bronchiolitis. To further understand the mechanisms leading to small airway fibrosis, a murine model was employed to show that sustained club cell injury elicited acute weight loss, caused increased local production of proinflammatory cytokines, and promoted accumulation of numerous myeloid cell subsets in the lung. Transition to a chronic phase was characterized by up-regulated expression of oxidative stress–associated genes, increased activation of transforming growth factor-β, accumulation of alternatively activated macrophages, and enhanced peribronchiolar collagen deposition. Comparative histopathologic analysis demonstrated that sustained club cell injury was sufficient to induce epithelial metaplasia, airway wall thickening, peribronchiolar infiltrates, and clusters of intraluminal airway macrophages that recapitulated key abnormalities observed in DRCB. Depletion of alveolar macrophages in mice decreased activation of transforming growth factor-β and ameliorated constrictive bronchiolitis. Collectively, these findings implicate sustained club cell injury in the development of DRCB and delineate pathways that may yield biomarkers and treatment targets for this disorder.