| Autor: |
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 |
| Předmět: |
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| Zdroj: |
American Journal of Respiratory & Critical Care Medicine; 6/15/2023, Vol. 207 Issue 12, p1576-1590, 55p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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