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- Title
CEACAM6 as a Novel Therapeutic Target to Boost HO-1—mediated Antioxidant Defense in COPD.
- Authors
Cheng-Yu Wu; Cilic, Anis; Pak, Oleg; Dartsch, Ruth Charlotte; Wilhelm, Jochen; Wujak, Magdalena; Lo, Kevin; Brosien, Monika; Ruoyu Zhang; Alkoudmani, Ibrahim; Witte, Biruta; Pedersen, Frauke; Watz, Henrik; Voswinckel, Robert; Günther, Andreas; Ghofrani, Hossein A.; Brandes, Ralf P.; Schermuly, Ralph T.; Grimminger, Friedrich; Seeger, Werner
- Abstract
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 nonsusceptible 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. Measurements and Main Results: 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. Conclusions: CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.
- Subjects
TOBACCO smoke pollution; CHRONIC obstructive pulmonary disease; CELL adhesion molecules; DEFENSE mechanisms (Psychology); CARCINOEMBRYONIC antigen
- Publication
American Journal of Respiratory & Critical Care Medicine, 2023, Vol 207, Issue 12, p1576
- ISSN
1073-449X
- Publication type
Article
- DOI
10.1164/rccm.202208-1603OC