Unravelling susceptibility to COPD: insights from a novel in vitro model to potential therapeutic targets

Long-term exposure to noxious gases and particulate matter from cigarette smoke (CS) or air pollution is a major cause of chronic obstructive pulmonary disease (COPD). However, only a portion of smokers develop the disease. Besides, COPD progression trajectories vary among patients. The molecular mechanisms underlying susceptibility to COPD development and progression remain largely undefined. To study the mechanisms of resistance against CS, an in vitro model of a CS-resistant cell line was recently established by our laboratory. Transcriptomic profiles between resistant and control cells were analysed and compared. Human lung samples were obtained to verify the findings from our in vitro model. Following our previous work, further studies on protein homeostasis were conducted using inhibitors of protein synthesis and degradation. Resistant phenotype was conferred by an enhanced heme oxygenase-1 (HO-1)-mediated antioxidant defence. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) was identified as a novel repressor of HO-1. Moreover, adeno-associated virus (AAV)-mediated CEACAM6 overexpression sensitised precision-cut lung slices (PCLS) from healthy donor lungs to CS-induced damage. Strikingly, HO-1 was regulated at post-transcriptional level in the resistant cells, accompanied by distinct patterns of HO-1 protein synthesis and degradation. Our research takes a significant step toward unravelling the complex mechanisms of CS-induced chronic lung diseases. The discovery of CEACAM6, and new insights into the post-transcriptional regulation of HO-1 protein in CS-resistant cells may lay the groundwork for further therapeutic strategies tailored to susceptible individuals.