Department of Pediatrics, University of Rochester Medical Center, Rochester, New York.
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York.
Am J Physiol Lung Cell Mol Physiol. 2022 Nov 1;323(5):L578-L592. doi: 10.1152/ajplung.00124.2022. Epub 2022 Sep 6.
Bronchiolitis obliterans (BO) is a debilitating disease of the small airways that can develop following exposure to toxic chemicals as well as respiratory tract infections. BO development is strongly associated with diacetyl (DA) inhalation exposures at occupationally relevant concentrations or severe influenza A viral (IAV) infections. However, it remains unclear whether lower dose exposures or more mild IAV infections can result in similar pathology. In the current work, we combined these two common environmental exposures, DA and IAV, to test whether shorter DA exposures followed by sublethal IAV infection would result in similar airways disease. Adult mice exposed to DA vapors 1 h/day for 5 consecutive days followed by infection with the airway-tropic IAV H3N2 (HKx31) resulted in increased mortality, increased bronchoalveolar lavage (BAL) neutrophil percentage, mixed obstruction and restriction by lung function, and subsequent airway remodeling. Exposure to DA or IAV alone failed to result in significant pathology, whereas mice exposed to DA + IAV showed increased α-smooth muscle actin (αSMA) and epithelial cells coexpressing the basal cell marker keratin 5 (KRT5) with the club cell marker SCGB1A1. To test whether DA exposure impairs epithelial repair after IAV infection, mice were infected first with IAV and then exposed to DA during airway epithelial repair. Mice exposed to IAV + DA developed similar airway remodeling with increased subepithelial αSMA and epithelial cells coexpressing KRT5 and SCGB1A1. Our findings reveal an underappreciated concept that common environmental insults while seemingly harmless by themselves can have catastrophic implications on lung function and long-term respiratory health when combined.
闭塞性细支气管炎（BO）是一种小气道的进行性疾病，可由接触有毒化学物质以及呼吸道感染引起。BO 的发展与职业相关浓度的二乙酰（DA）吸入暴露或严重的甲型流感病毒（IAV）感染密切相关。然而，目前尚不清楚低剂量暴露或更温和的 IAV 感染是否会导致类似的病理学改变。在目前的工作中，我们将这两种常见的环境暴露，即 DA 和 IAV，结合起来，以测试较短时间的 DA 暴露后，再受到低剂量的 IAV 感染是否会导致类似的气道疾病。连续 5 天每天 1 小时暴露于 DA 蒸气后，再感染气道嗜性 IAV H3N2（HKx31）的成年小鼠，死亡率增加，支气管肺泡灌洗液（BAL）中性粒细胞百分比增加，混合性阻塞和肺功能受限，以及随后的气道重塑。单独暴露于 DA 或 IAV 均未导致明显的病理学改变，而暴露于 DA+IAV 的小鼠则显示出α-平滑肌肌动蛋白（αSMA）和上皮细胞共表达基底细胞标志物角蛋白 5（KRT5）与杯状细胞标志物 SCGB1A1 的增加。为了测试 DA 暴露是否会损害 IAV 感染后的上皮修复，我们首先用 IAV 感染小鼠，然后在气道上皮修复期间暴露于 DA。感染 IAV+DA 的小鼠表现出类似的气道重塑，其上皮下的αSMA 和共表达 KRT5 和 SCGB1A1 的上皮细胞增加。我们的研究结果揭示了一个被低估的概念，即看似无害的常见环境刺激物，如果同时发生，可能会对肺功能和长期呼吸健康产生灾难性的影响。
