Dynamic analysis of gene signatures in the progression of chronic obstructive pulmonary disease

Purpose Oxidative stress is an important amplifying mechanism in chronic obstructive pulmonary disease (COPD), however, it is unclear how oxidative stress changes and its exact amplification mechanism in pathological process. We aimed to dynamically analyze the progression of COPD and further elucidate the characteristics of each developmental stage and unveil the underlying mechanisms.

Methods We performed a holistic analysis by integrating GEO microarray datasets related to smoking, emphysema, and GOLD classification based on the concept of gene, environment and time (GET). Gene Ontology (GO), protein-protein interaction (PPI) networks and gene set enrichment analysis (GSEA) were used to explore the changing characteristics and potential mechanisms. Using lentivirus to promote HIF3A overexpression.

Results In smokers versus nonsmokers, GO term mainly enriched in “negative regulation of apoptotic process”. In later transitions between stages, the main enriched terms were continuous progression of “oxidation-reduction process”, and “cellular response to hydrogen peroxide”. Logistic regression showed that these core DEGs had diagnostic accuracy in test (AUC=0.823) and validation (AUC=0.750) sets. GSEA and PPI network showed one of the core DEGs, HIF3A, strongly interacted with the ubiquitin-mediated proteolysis pathway. Overexpression of HIF3A restored SOD levels and alleviated the ROS accumulation caused by CSE treatment.

Conclusion Oxidative stress was continuously intensified from mild emphysema to GOLD-4, thus, special attention should be paid to the identification of emphysema. Furthermore, the downregulated HIF3A may play an important role in the intensified oxidative stress in COPD.