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Cheng-Yu Wu, Anis Cilic, O. Pak, R. Dartsch, J. Wilhelm, M. Wujak, Kevin Lo, M. Brosien, Ruoyu Zhang, I. Alkoudmani, B. Witte, F. Pedersen, H. Watz, R. Voswinckel, Andreas Günther, H. Ghofrani, R. Brandes, R. Schermuly, F. Grimminger, W. Seeger, N. Sommer, N. Weissmann, S. Hadzic
3 23. 5. 2023.

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

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 non-susceptible 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 (hPCLS). MEASUREMENTS AND MAIN RESULTS 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE was attenuated, paralleled by profound upregulation of heme-oxygenase-1 (HO-1). We identified carcinoembryonic-antigen-related-cell-adhesion-molecule-6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2). Consistently, inhibition of HO-1 activity in hAEC2 increased the susceptibility towards CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in hPCLS upon CSE treatment. CONCLUSIONS CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.


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