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

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

doi:10.1164/rccm.202208-1603OC

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

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Seeger, Werner
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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引用

Wu, C.-Y., Cilic, A., Pak, O., Dartsch, R. C., Wilhelm, J., Wujak, M., Lo, K., Brosien, M., Zhang, R., Alkoudmani, I., Witte, B., Pedersen, F., Watz, H., Voswinckel, R., Unther, A. G., Ghofrani, H. A., Brandes, R. P., Schermuly, R. T., Grimminger, F., Seeger, W., Sommer, N., Weissmann, N., & 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. doi:10.1164/rccm.202208-1603OC.

引用: https://hdl.handle.net/21.11116/0000-000D-7EB7-8

要旨

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.