Vose Aaron, Birukova Anastasiya, Albright Michaela, Schlobohm Adam, Garantziotis Stavros, Tata Purushothama Rao, Barkauskas Christina, Tighe Robert
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, North Carolina.
Biogen, Research Triangle Park, North Carolina.
Am J Respir Cell Mol Biol. 2025 Jul;73(1):109-119. doi: 10.1165/rcmb.2024-0385OC.
Becoming more frequent because of climate change, ozone (O) exposures can cause lung injury. Alveolar type 2 (AT2) cells and hyaluronan (HA), a matrix component, are critical to repairing lung injury and restoring homeostasis. Here, we define the impact of HA on AT2 cells after acute O exposure. C57BL/6J mice were exposed to filtered air or O (2 ppm) for 3 hours. HA was measured in BAL and lung tissue; HAS (HA synthase) 1, 2, and 3 and HYAL (hyaluronidase) 1, 2, and 3 mRNA were measured in lung tissue and BAL cells. At 48 to 72 hours after O exposure, HA increased in BAL fluid by ELISA and lung tissue by immunohistochemistry, with new HA deposition localized to the alveolar ducts. This was associated with increased whole-lung HAS2 mRNA expression. Using an AT2 lineage reporter () mouse strain, we noted that proliferating AT2 cells colocalized with O-induced HA deposition in the alveolar duct region. In addition, AT2-to-AT1 cell differentiation after O was noted. To determine whether O-induced HA alters AT2 cell function, we inhibited HA-AT2 interaction with a synthetic inhibitor (Pep-1), which diminished AT2 proliferation. Mice treated with Pep-1 after O exposure demonstrated increased BAL albumin concentration compared with filtered air exposure, suggesting that inhibition of HA-AT2 cell interactions resulted in persistent alveolar-capillary permeability and diminished resolution of O-induced lung injury. Overall, the findings suggest that HA increases in the alveolar duct after acute O exposure and that HA-AT2 cell interactions are required for resolution of acute O-induced lung injury.
由于气候变化，臭氧（O）暴露变得更加频繁，可导致肺损伤。肺泡II型（AT2）细胞和透明质酸（HA，一种基质成分）对于修复肺损伤和恢复内环境稳态至关重要。在此，我们确定急性O暴露后HA对AT2细胞的影响。将C57BL/6J小鼠暴露于过滤空气或O（2 ppm）中3小时。在支气管肺泡灌洗（BAL）液和肺组织中测量HA；在肺组织和BAL细胞中测量HA合酶（HAS）1、2和3以及透明质酸酶（HYAL）1、2和3的mRNA。在O暴露后48至72小时，通过酶联免疫吸附测定（ELISA）发现BAL液中HA增加，通过免疫组织化学发现肺组织中HA增加，新的HA沉积定位于肺泡管。这与全肺HAS2 mRNA表达增加有关。使用AT2谱系报告基因（）小鼠品系，我们注意到增殖的AT2细胞与肺泡管区域中O诱导的HA沉积共定位。此外，还观察到O暴露后AT2向AT1细胞的分化。为了确定O诱导的HA是否改变AT2细胞功能，我们用一种合成抑制剂（Pep-1）抑制HA与AT2的相互作用，这减少了AT2的增殖。O暴露后用Pep-1处理的小鼠与暴露于过滤空气的小鼠相比，BAL白蛋白浓度增加，这表明抑制HA与AT2细胞的相互作用导致肺泡 - 毛细血管通透性持续增加，并且O诱导的肺损伤的消退减弱。总体而言，这些发现表明急性O暴露后肺泡管中HA增加，并且HA与AT2细胞的相互作用是急性O诱导的肺损伤消退所必需的。
