CYP1B1 modulates stress and repair pathways in airway cells challenged by wood smoke particles

Environmental pollution negatively impacts respiratory health by damaging and reprogramming airway epithelial cells (AECs). CYP1B1 is one of the most highly induced genes in AECs exposed to combustion-derived air pollutants such as wood smoke particulate matter (WSPM) and plays dual roles in generating toxic reactive intermediates and in the detoxification of xenobiotics of diverse nature. However, the significance of CYP1B1 induction by AECs challenged with pollutants remains unclear. A comparison of BEAS-2B and CYP1B1-overexpressing BEAS-2B cells revealed that CYP1B1 overexpression reduced acute cytotoxicity and enhanced proliferation and migration following WSPM-induced injury in vitro. Conversely, inhibition of CYP1B1 in HBEC3-KT cells increased cytotoxicity and decreased proliferation. CYP1B1 inhibition in HBEC3-KT cells exacerbated endoplasmic reticulum stress (ERS), which promotes cell cycle arrest and cytotoxicity, while overexpression of CYP1B1 attenuated ERS. CYP1B1 Inhibition also enhanced the expression of mRNA for the NRF2 target genes NQO1 and HMOX1, and the proinflammatory cytokine IL8, whereas CYP1B1 overexpression downregulated mRNA expression for NQO1 and HMOX1. In vivo, Cyp1b1-deficient mice exhibited greater basal lung inflammation, but limited response to WSPM-treatment compared with wild-type mice. However, Cyp1b1-/- derived mouse tracheal epithelial cells treated with WSPM showed a more pronounced inflammatory response, characterized by exacerbated Cxcl1, Cxcl2, and Trpa1 mRNA expression compared with wild-type cells. In conclusion, CYP1B1 mitigates WSPM-induced damage to AECs by squelching ERS, oxidative stress, NRF2, and inflammatory signaling, thereby supporting cellular defense and repair. Additional interactions with CYP1A1 and TRP channels also suggest a broader role in AEC physiology.