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

Area of Science:

• Pulmonary toxicology
• Cellular and molecular biology
• Extracellular matrix research

Background:

• Climate change increases ozone (O3) exposure frequency, leading to lung injury.
• Alveolar type 2 (AT2) cells and hyaluronan (HA) are crucial for lung repair and homeostasis.
• The specific role of HA in AT2 cell function post-ozone exposure requires elucidation.

Purpose of the Study:

• To define the impact of hyaluronan (HA) on alveolar type 2 (AT2) cells following acute ozone (O3) exposure.
• To investigate the localization and dynamics of HA deposition after O3 inhalation.
• To determine the necessity of HA-AT2 cell interactions for resolving ozone-induced lung injury.

Main Methods:

• Exposure of C57BL/6J mice to filtered air (FA) or ozone (O3) (2 ppm) for 3 hours.
• Quantification of HA in bronchoalveolar lavage (BAL) fluid and lung tissue.
• Measurement of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-3) mRNA expression.
• Utilized AT2 lineage reporter mice (Sftpc-CreER;Rosa-Tm) to track AT2 cell proliferation and differentiation.
• Inhibition of HA-AT2 interactions using a synthetic inhibitor (Pep-1) to assess functional consequences.

Main Results:

• Ozone exposure significantly increased HA levels in BAL fluid and lung tissue, with deposition localized to alveolar ducts.
• Increased HAS2 mRNA expression correlated with HA deposition post-ozone exposure.
• Proliferating AT2 cells were found in proximity to ozone-induced HA deposits, and AT2 to AT1 cell differentiation was observed.
• Inhibition of HA-AT2 interactions with Pep-1 reduced AT2 cell proliferation.
• Pep-1 treatment post-ozone exposure led to increased BAL albumin levels, indicating persistent alveolar-capillary permeability and impaired injury resolution.

Conclusions:

• Acute ozone exposure increases hyaluronan deposition in the alveolar duct region.
• Hyaluronan-AT2 cell interactions are essential for the proliferation of AT2 cells following ozone injury.
• These HA-AT2 cell interactions are critical for the resolution of acute ozone-induced lung injury and maintaining alveolar-capillary barrier integrity.