MOLECULAR CROSSTALK BETWEEN PULMONARY AND CARDIOVASCULAR DISORDERS: A SYSTEMIC APPROACH

Abstract

Chronic Obstructive Pulmonary Disease (COPD) can co-occur with cardiovascular disease (CVD) in the elderly, raising the possibility of common molecular pathways between the two diseases. Pulmonary inflammation and cardiovascular dysfunction are clinically important and the molecular mechanisms that connect these processes are still not fully understood. This dissertation provides a thorough systems biology study of the molecular crosstalk between COPD and CVD using integrative computational methods such as transcriptomic analysis, network topology analysis, and pathway enrichment. To identify the common inflammatory mediators of COPD-CVD comorbidity we combined data from public gene expression datasets, publicly available lists of inflammatory genes, and network and pathway-based analyses in a novel systems biology approach. By integrating transcriptomic data from pulmonary and cardiovascular sources, we aimed to reveal conserved inflammatory pathways and molecules that are simultaneously expressed during both diseases. This method provided the ability to uncover common molecular inflammatory signatures in addition to those that may be more specifically related to either COPD or CVD, thereby shedding light on inter-organ inflammation signaling between the lungs and the heart. The central inflammatory molecule identifying multiple immune and cardiovascular signaling pathways, through network analysis, was found to be interleukin-6 (IL-6) and identified as a crucial bridge between NF-KB, JAK-STAT, ICAM-1 immune and vascular signaling pathways, all of which are essential for the enhancement of inflammation, recrutement of immune cells and endothelial dysfunction and vascular remodeling. Pathway enrichment analysis showed a simultaneous activation of both pro- and anti inflammatory pathways (IL-4/IL-13 and IL-10), suggesting immune dysregulation instead of a one-way inflammatory shift. It is suggested that this simultaneous activation of opposing cytokine pathways can be responsible for chronic tissue remodelling, endothelial dysfunction and chronic inflammation that occurs in both COPD and CVD. These results suggest that the inflammatory regulatory axis centred on IL-6 is a potential therapeutic target for multiple diseases. Translational opportunities are discussed, such as strategies like monoclonal antibody-induced IL-6 inhibition or inhibition of IL-6 receptor, or inhibition of JAK/STAT pathway and RNA interference-based IL-6. This dissertation makes a contribution to understanding of the pulmonary-cardiovascular comorbidity in the context of inflammaging and age-related disease, and provides a framework for future experimental validation.