Journal article

Authors list: Wu, Cheng-Yu; Cilic, Anis; Pak, Oleg; Dartsch, Ruth Charlotte; Wilhelm, Jochen; Wujak, Magdalena; Lo, Kevin; Brosien, Monika; Zhang, Ruoyu; Alkoudmani, Ibrahim; Witte, Biruta; Pedersen, Frauke; Watz, Henrik; Voswinckel, Robert; Unther, Andreas G.; Ghofrani, Hossein A.; Brandes, Ralf P.; Schermuly, Ralph T.; Grimminger, Friedrich; Seeger, Werner; Sommer, Natascha; Weissmann, Norbert; Hadzic, Stefan

Publication year: 2023

Pages: 1576-1590

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 207

Issue number: 12

ISSN: 1073-449X

eISSN: 1535-4970

Open access status: Hybrid

DOI Link: https://doi.org/10.1164/rccm.202208-1603OC

Publisher: American Thoracic Society

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; smoker1COPD, 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.

Harvard Citation style: Wu, C., Cilic, A., Pak, O., Dartsch, R., Wilhelm, J., Wujak, M., et al. (2023) CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD, American Journal of Respiratory and Critical Care Medicine, 207(12), pp. 1576-1590. https://doi.org/10.1164/rccm.202208-1603OC

APA Citation style: Wu, C., Cilic, A., Pak, O., Dartsch, R., Wilhelm, J., Wujak, M., Lo, K., Brosien, M., Zhang, R., Alkoudmani, I., Witte, B., Pedersen, F., Watz, H., Voswinckel, R., Unther, A., Ghofrani, H., Brandes, R., Schermuly, R., Grimminger, F., ...Hadzic, S. (2023). CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD. American Journal of Respiratory and Critical Care Medicine. 207(12), 1576-1590. https://doi.org/10.1164/rccm.202208-1603OC