TNFRSF12A and CD38 Contribute to a Vicious Circle for Chronic Obstructive Pulmonary Disease by Engaging Senescence Pathways

Abstract

Pathogenesis of chronic obstructive pulmonary disease (COPD) is dependent on chronic inflammation and is hypothesized to represent organ-specific senescence phenotype. Identification of senescence-associated gene drivers for the development of COPD is warranted. By employing automated pipeline, we have compiled lists of the genes implicated in COPD (N = 918) and of the genes changing their activity along with cell senescence (N = 262), with a significant (p < 7.06e–60) overlap between these datasets (N = 89). A mega-analysis and a partial mega-analysis were conducted for gene sets linked to senescence but not yet to COPD, in nine independent mRNA expression datasets comprised of tissue samples of COPD cases (N = 171) and controls (N = 256). Mega-analysis of expression has identified CD38 and TNFRSF12A (p < 2.12e–8) as genes not yet explored in a context of senescence–COPD connection. Functional pathway enrichment analysis allowed to generate a model, which explains accelerated aging phenotypes previously observed in COPD patients. Presented results call for investigation of the role of TNFRSF12A/CD38 balance in establishing a vicious cycle of unresolvable tissue remodeling in COPD lungs.