ERS 2024: Unravelling Susceptibility to COPD: Insights from a Novel in Vitro Model to Potential Therapeutic Targets

Speaker: Cheng-Yu Wu

A study titled "Unraveling Susceptibility to Chronic obstructive pulmonary disease (COPD): Insights from a Novel In-Vitro Model to Potential Therapeutic Targets" was discussed during the session. It was highlighted that chronic lung disease development, such as COPD, may be influenced by genetic predisposition and the interaction between external exposures and genes throughout a person's lifetime. The session aimed to identify potential therapeutic strategies to address the treatment or potential cure of COPD. Nitrosative oxidative stress, caused by high levels of reactive nitrogen and oxygen species, such as nitric oxide and superoxide, was identified as one of the external stressors contributing to COPD development. A marker of this stress, 3-nitrotyrosine, was found to be elevated in smokers with COPD compared to smokers without COPD. The observation raised questions about whether a coping mechanism exists that protects some smokers from developing the disease. A novel in vitro model of a cigarette smoke-resistant cell line was established to investigate this. It was observed that these resistant cells exhibited lower nitrosative oxidative stress and higher antioxidant defense, mediated by heme oxygenase 1 (HO-1). 

Transcriptome profiling revealed a significant downregulation of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in the resistant cells, a finding that was validated using Precision Cut Lung Slices (PCLS). Upon overexpression of CEACAM6 and exposure to cigarette smoke, decreased HO-1 levels, increased nitrosative oxidative stress, and increased cytotoxicity were noted. Further investigations into the clinical relevance of CEACAM6 were conducted using human peripheral blood mononuclear cells (hPBMC). It was found that CEACAM6 levels correlated with HO-1 levels and lung function in hPBMC, suggesting that CEACAM6 could serve as a potential biomarker. In conclusion, nitrosative oxidative stress was identified as a contributor to COPD development. The novel in vitro model demonstrated that enhanced antioxidant defense could protect susceptible smokers from disease development, while CEACAM6 was shown to impair this defense. Therefore, targeting the CEACAM6 and HO-1 axis was proposed as a potential therapeutic approach for COPD. 

European Respiratory Society Congress 2024, 7–11 September, Vienna, Austria.