CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Abstract

<b>Rationale:</b> 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 nonsusceptible smokers to COPD remain largely unresolved. <b>Objectives:</b> To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. <b>Methods:</b> Four cohorts were investigated: <i>1</i>) sputum samples (healthy, <i>n</i> = 4; COPD, <i>n</i> = 37), <i>2</i>) lung tissue samples (healthy, <i>n</i> = 13; smokers without COPD, <i>n</i> = 10; smoker+COPD, <i>n</i> = 17), <i>3</i>) pulmonary lobectomy tissue samples (no/mild emphysema, <i>n</i> = 6), and <i>4</i>) blood samples (healthy, <i>n</i> = 6; COPD, <i>n</i> = 18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel <i>in vitro</i> 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 <i>ex vivo</i> model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices. <b>Measurements and Main Results:</b> 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE treatment was attenuated, paralleled by profound upregulation of heme oxygenase-1 (HO-1). We identified carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2s). Consistently, inhibition of HO-1 activity in hAEC2s increased the susceptibility toward CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in human precision-cut lung slices on CSE treatment. <b>Conclusions:</b> CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.