Hyaluronan Directs Alveolar Type II Cell Response to Acute Ozone Exposure in Mice.

Abstract

Becoming more frequent due to climate change, ozone (O₃) 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 following acute O₃ exposure. C57BL/6J mice were exposed to filtered air (FA) or O₃ (2 ppm) for 3h. Hyaluronan was measured in bronchoalveolar lavage (BAL) and lung tissue; hyaluronan synthases (HAS1, 2, and 3) and hyaluronidases (HYAL1, 2, and 3) mRNA were measured in lung tissue and BAL cells. At 48-72h post O₃ 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 a AT2 lineage reporter (Sftpc-CreER;Rosa-Tm) mouse strain, we noted that proliferating AT2 cells co-localized with O₃-induced HA deposition in the alveolar duct region. Additionally, AT2 to AT1 cell differentiation following O₃ was noted. To determine whether O₃-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 following O₃ exposure demonstrated increased BAL albumin levels as compared to FA exposure, suggesting that inhibition of HA-AT2 cell interactions resulted in persistent alveolar-capillary permeability and diminished resolution of O₃-induced lung injury. Overall, the findings suggest that HA increases in the alveolar duct following acute O₃ exposure and that HA-AT2 cell interactions are required for resolution of acute O₃-induced lung injury.