Novel COPD therapy suggested via RIPK1 kinase inhibition

Prof Phil Hansbro

Australian researchers have identified a potential new therapeutic approach for COPD through the targeting and inhibition of a protein called RIPK1.

Using experimental models of COPD, a team led by Professor Phil Hansbro, Director of the Centenary UTS Centre for Inflammation, Sydney showed that RIPK1 kinase inhibition was protective against the development of airways inflammation, emphysema and lung function decline.

Reporting their findings in the European Respiratory Journal (link here) the researchers also documented increased levels of the protein RIPK1 in the lungs of people with COPD as well as in experimental COPD mouse models.

In their study, the team, in conjunction with researchers at Ghent University, Belgium, assessed RIPK1 expression in RNA-sequencing data from human and mouse lungs and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry.

They also assessed the consequences of genetic and drug inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1 kinase deficient mice and the RIPK1 kinase inhibitor GSK’547.

The results showed that RIPK1 expression was increased in alveolar type I (AT1), AT2, ciliated and neuroendocrine cells in human COPD.

RIPK1 protein levels were significantly increased in airway epithelium of COPD patients, compared to never smokers and smokers without airflow limitation.

Exposure to cigarette smoke was shown to increase Ripk1 expression in AT2 cells as well as in alveolar macrophages and T cells.

Professor Hansbro and colleagues showed that genetic and drug inhibition of RIPK1 kinase activity significantly attenuated airway inflammation in response to acute and subacute cigarette smoke exposure, as well as airway remodelling, emphysema and apoptotic and necroptotic cell death upon chronic smoke exposure.

RIPK1 kinase inhibition also significantly attenuated elastase-induced emphysema and lung function decline.

Analysis of lung tissue from cigarette smoke-exposed mice further revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.

Professor Hansbro concluded that the findings suggested that r RIPK1 kinase inhibition may “represent a novel promising therapeutic approach” for prevention of COPD.

Although the experimental drug was donated by GSK, the study authors declared no commercial or financial conflicts of interest in the funding, design or analysis of the study.

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