Hyaluronan Signaling Ameliorates the Epithelial Injury Response and Barrier Disruption After Ozone Exposure

Area of Science:

• Pulmonary toxicology
• Cellular biology
• Immunology

Background:

• Airway pollutants like ozone induce lung injury, exacerbating conditions such as asthma and COPD.
• Epithelial dysfunction is a key factor in ozone-induced lung injury, but underlying mechanisms require further elucidation.
• The extracellular matrix component hyaluronan (HA) is implicated in cellular injury responses.

Purpose of the Study:

• To investigate the role of hyaluronan (HA) signaling in mediating epithelial responses to ozone-induced lung injury.
• To explore the therapeutic potential of high molecular weight HA (HMWHA) in protecting against ozone-induced epithelial damage.

Main Methods:

• Exposed human and murine differentiated primary epithelia to ozone in vitro.
• Assessed epithelial integrity and transcriptomic changes post-exposure.
• Utilized genetically modified cells deficient in HA receptors (CD44, RHAMM) and innate immune receptors (TLR4, TLR5).
• Evaluated the protective effects of HMWHA.

Main Results:

• Ozone exposure significantly reduced epithelial integrity and induced comparable inflammatory changes in both human and murine cells.
• CD44 deficiency mitigated inflammation, whereas RHAMM deficiency worsened cell injury.
• HMWHA demonstrated protective effects against ozone-induced epithelial injury.
• HMWHA-mediated protection was dependent on TLR4 and TLR5 activation, independent of CD44 and RHAMM.

Conclusions:

• Hyaluronan signaling pathways contribute significantly to ozone-induced epithelial injury.
• High molecular weight hyaluronan (HMWHA) protects lung epithelia from ozone damage.
• HMWHA exerts its protective effects through the activation of innate immune receptors TLR4 and TLR5.