CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.
RATIONALE Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in non-susceptible smokers to COPD remain largely unresolved. OBJECTIVES To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. METHODS Four cohorts were investigated: (1) sputum samples (healthy, n=4; COPD, n=37), (2) lung tissue samples (healthy, n=13; smokers without COPD, n=10; smoker+COPD, n=17), (3) pulmonary lobectomy tissue samples (no/mild emphysema, n=6) and (4) blood samples (healthy, n=6; COPD, n=18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices (hPCLS). MEASUREMENTS AND MAIN RESULTS 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE was attenuated, paralleled by profound upregulation of heme-oxygenase-1 (HO-1). We identified carcinoembryonic-antigen-related-cell-adhesion-molecule-6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2). Consistently, inhibition of HO-1 activity in hAEC2 increased the susceptibility towards CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in hPCLS upon CSE treatment. CONCLUSIONS CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.