| Autor: |
Zhe Lu, Van Eeckhoutte, Hannelore P., Gang Liu, Nair, Prema M., Jones, Bernadette, Gillis, Caitlin M., Nalkurthi, B. Christina, Verhamme, Fien, Buyle-Huybrecht, Tamariche, Vandenabeele, Peter, Berghe, Tom Vanden, Brusselle, Guy G., Horvat, Jay C., Murphy, James M., Wark, Peter A., Bracke, Ken R., Fricker, Michael, Hansbro, Philip M., Lu, Zhe, Liu, Gang |
| Předmět: |
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| Zdroj: |
American Journal of Respiratory & Critical Care Medicine; 9/15/2021, Vol. 204 Issue 6, p667-681, 47p |
| Abstrakt: |
Rationale: Necroptosis, mediated by RIPK3 and MLKL, is a form of regulated necrosis that can drive tissue inflammation and destruction, however its contribution to COPD pathogenesis is poorly understood.Objectives: To determine the role of necroptosis in COPD.Methods: Levels of RIPK3, MLKL and activated phospho-MLKL were measured in lung tissues of COPD patients and non-COPD controls. Necroptosis-related mRNA and proteins and cell death were examined in the lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3- and Mlkl-deficient (-/-) mice to CS exposure were compared to wild-type mice. Combined inhibition of apoptosis (pan-caspase inhibitor qVD-OPh) and necroptosis (Mlkl-/- mice) was assessed.Measurements and Main Results: Protein levels of MLKL and pMLKL but not RIPK3 were increased in lung tissues of COPD patients compared to never smokers or smoker non-COPD controls. Necroptosis-related mRNA and protein levels were increased in lung tissue and macrophages in CS-exposed mice/experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation in response to acute CS-exposure. Ripk3 deficiency reduced airway inflammation and remodelling and development of emphysematous pathology following chronic CS-exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodelling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung cell death.Conclusions: Necroptosis is induced by CS exposure and increased in COPD patient lungs and experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodelling and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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