Wicher Sarah A, Jacoby David B, Fryer Allison D
Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon; and.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, Oregon.
Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L969-L982. doi: 10.1152/ajplung.00530.2016. Epub 2017 Mar 3.
Ozone causes vagally mediated airway hyperreactivity and recruits inflammatory cells, including eosinophils, to lungs, where they mediate ozone-induced hyperreactivity 1 day after exposure but are paradoxically protective 3 days later. We aimed to test the role of newly divided eosinophils in ozone-induced airway hyperreactivity in sensitized and nonsensitized guinea pigs. Nonsensitized and sensitized guinea pigs were treated with 5-bromo-2-deoxyuridine (BrdU) to label newly divided cells and were exposed to air or ozone for 4 h. Later (1 or 3 days later), vagally induced bronchoconstriction was measured, and inflammatory cells were harvested from bone marrow, blood, and bronchoalveolar lavage. Ozone induced eosinophil hematopoiesis. One day after ozone, mature eosinophils dominate the inflammatory response and potentiate vagally induced bronchoconstriction. However, by 3 days, newly divided eosinophils have reached the lungs, where they inhibit ozone-induced airway hyperreactivity because depleting them with antibody to IL-5 or a TNF-α antagonist worsened vagally induced bronchoconstriction. In sensitized guinea pigs, both ozone-induced eosinophil hematopoiesis and subsequent recruitment of newly divided eosinophils to lungs 3 days later failed to occur. Thus mature eosinophils dominated the ozone-induced inflammatory response in sensitized guinea pigs. Depleting these mature eosinophils prevented ozone-induced airway hyperreactivity in sensitized animals. Ozone induces eosinophil hematopoiesis and recruitment to lungs, where 3 days later, newly divided eosinophils attenuate vagally mediated hyperreactivity. Ozone-induced hematopoiesis of beneficial eosinophils is blocked by a TNF-α antagonist or by prior sensitization. In these animals, mature eosinophils are associated with hyperreactivity. Thus interventions targeting eosinophils, although beneficial in atopic individuals, may delay resolution of airway hyperreactivity in nonatopic individuals.
臭氧会引发迷走神经介导的气道高反应性，并将包括嗜酸性粒细胞在内的炎症细胞募集到肺部，这些炎症细胞在接触臭氧1天后介导臭氧诱导的高反应性，但在3天后却具有保护作用。我们旨在测试新分化的嗜酸性粒细胞在致敏和未致敏豚鼠臭氧诱导的气道高反应性中的作用。未致敏和致敏豚鼠用5-溴-2-脱氧尿苷（BrdU）处理以标记新分化的细胞，并暴露于空气或臭氧中4小时。之后（1天或3天后），测量迷走神经诱导的支气管收缩，并从骨髓、血液和支气管肺泡灌洗中收集炎症细胞。臭氧诱导嗜酸性粒细胞生成。臭氧暴露1天后，成熟嗜酸性粒细胞主导炎症反应并增强迷走神经诱导的支气管收缩。然而，到3天时，新分化的嗜酸性粒细胞已到达肺部，在那里它们抑制臭氧诱导的气道高反应性，因为用抗IL-5抗体或TNF-α拮抗剂耗尽它们会使迷走神经诱导的支气管收缩恶化。在致敏豚鼠中，臭氧诱导的嗜酸性粒细胞生成以及3天后新分化的嗜酸性粒细胞随后向肺部的募集均未发生。因此，成熟嗜酸性粒细胞主导了致敏豚鼠中臭氧诱导的炎症反应。耗尽这些成熟嗜酸性粒细胞可预防致敏动物中臭氧诱导的气道高反应性。臭氧诱导嗜酸性粒细胞生成并募集到肺部，3天后，新分化的嗜酸性粒细胞减弱迷走神经介导的高反应性。TNF-α拮抗剂或先前的致敏会阻断臭氧诱导的有益嗜酸性粒细胞生成。在这些动物中，成熟嗜酸性粒细胞与高反应性相关。因此，针对嗜酸性粒细胞的干预措施虽然对特应性个体有益，但可能会延迟非特应性个体气道高反应性的消退。
