Role Of The Kinase-Dependent Functions Of Ripk1 In Copd

Background: Disturbances in pulmonary cell death pathways in COPD may contribute to the ongoing inflammation and development of emphysema. Receptor interacting protein kinase-1 (RIPK1) has an essential role in regulating inflammation and cell death. The kinase-dependent functions of RIPK1 are required for its killing potential, through the induction of necroptosis, apoptosis or pyroptosis. Objectives: We investigated the levels of RIPK1 in human COPD and assessed the consequences of a defective kinase function of RIPK1 in two mouse models of COPD. Methods: Protein levels of RIPK1 were evaluated by IHC in lungs of 8 never smokers, 16 smokers and 24 patients with COPD GOLD II to IV. RIPK1S25D/S25D mutant mice (defective in kinase activity) and control RIPK1+/+ littermates were either exposed to 4 weeks of air or cigarette smoke (CS) to study inflammation in the BAL, or to 3 intratracheal instillations of PBS or elastase to study pulmonary emphysema via lung function measurements (FlexiVent). Results: IHC revealed positive staining for RIPK1 in airway epithelial cells. Quantification demonstrated significantly higher RIPK1 protein levels in airway epithelium of smokers and COPD patients, compared to never smokers. In RIPK1S25D/S25D mice, the CS-induced increase in the percentage of BAL neutrophils was significantly attenuated compared to littermate controls. Finally, RIPK1S25D/S25D were protected against elastase-induced emphysema, evidenced by a significant attenuation of the increased compliance, decreased elasticity and left-upward shift in pressure-volume loops. Conclusion: We provide evidence that the kinase function of RIPK1 is involved in CS-induced pulmonary inflammation and elastase-induced emphysema.