Abstract
Chronic Obstructive Pulmonary Disease (COPD) is characterized by chronic inflammation of the lungs and exaggerated cell death, leading to emphysema and airway remodeling. We hypothesize that cigarette smoke (CS), the main risk factor for COPD, activates Receptor Interacting Protein Kinase-1 (RIPK1), a key regulator of inflammation and cell death. We investigated RIPK1 levels in lungs of patients with and without COPD and assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase function in short and long-term COPD mouse models. RIPK1 protein levels were significantly increased in airway epithelium of smokers and patients with COPD, compared to never smokers. In mice defective in RIPK1 kinase activity (Ripk1S25D/S25D) the pulmonary inflammation upon short-term (5 days or 4 weeks) CS-exposure was significantly attenuated compared to WT controls. Additionally, Ripk1S25D/S25D mice were protected against elastase-induced emphysema, evidenced by significantly improved lung function and a decreased mean linear intercept. Likewise, daily treatment with the GSK’547 RIPK1 kinase inhibitor attenuated pulmonary inflammation upon short-term CS-exposure and protected against development of emphysema and airway remodeling upon chronic (8 weeks) CS-exposure. However, RIPK1 kinase inhibition significantly amplified the pulmonary inflammation upon chronic CS-exposure, likely due to exaggerated cellular senescence, as was already observed by RNA sequencing upon short-term CS-exposure. In conclusion, RIPK1 kinase inhibition protects against CS-induced pulmonary inflammation, emphysema and remodeling, but long-term inhibition may result in increased senescence-associated inflammation.
Footnotes
Cite this article as ERJ Open Research 2022; 8: Suppl. 8, 19.
This article was presented at the 2022 ERS Lung Science Conference, in session “Poster Session 2”.
This is an ERS Lung Science Conference abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2022