Integrating 3-omics data analyze rat lung tissue of COPD states and medical intervention by delineation of molecular and pathway alterations.

Liping Yang,Yange Tian,Ya Li,Jiansheng Li,Yunping Bai,Suyun Li,Peng Zhao

doi:10.1042/bsr20170042

Abstract

Chronic obstructive pulmonary disease (COPD) is a serious health problem. However, the molecular pathogenesis of COPD remains unknown. Here, we explored the molecular effects of cigarette smoke and bacterial infection in lung tissues of COPD rats. We also investigated therapeutic effects of aminophylline (APL) on the COPD rats and integrated transcriptome, proteome, and metabolome data for a global view of molecular mechanisms of COPD progression. Using molecular function and pathway analyses, the genes and proteins regulated in COPD and APL-treated rats were mainly attributed to oxidoreductase, antioxidant activity, energy and fatty acid metabolism. Furthermore, we identified hub proteins such as Gapdh (glyceraldehyde-3-phosphate dehydrogenase), Pkm (pyruvate kinase isozymes M1/M2), and Sod1 (superoxide dismutase 1), included in energy metabolism and oxidative stress. Then, we identified the significantly regulated metabolic pathways in lung tissues of COPD- and APL-treated rats, such as arachidonic acid, linoleic acid, and α-linolenic acid metabolism, which belong to the lipid metabolism. In particular, we picked the arachidonic acid metabolism for a more detailed pathway analysis of transcripts, proteins, and metabolites. We could observe an increase in metabolites and genes involved in arachidonic acid metabolism in COPD rats and the decrease in these in APL-treated rats, suggesting that inflammatory responses were up-regulated in COPD rats and down-regulated in APL-treated rats. In conclusion, these system-wide results suggested that COPD progression and its treatment might be associated with oxidative stress, lipid and energy metabolism disturbance. Additionally, we demonstrated the power of integrated omics for the elucidation of genes, proteins, and metabolites’ changes and disorders that were associated with COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is pathophysiologically characterized by chronic airflow limitation and progressive lung function decline resulting from an abnormal inflammatory response to inhaled particles and gases in the lung [1]
We found that APL significantly increased the tidal volume (TV) and peak expiratory flow (PEF) and slightly increased the 50% tidal volume expiratory flow (EF50) in COPD rats during week 20 to 32
Integrating transcriptomics, proteomics, and metabolomics data is becoming more important to analyze in mammalian tissues disease states and medical intervention in a preclinical setting

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is pathophysiologically characterized by chronic airflow limitation and progressive lung function decline resulting from an abnormal inflammatory response to inhaled particles and gases in the lung [1]. Extensive investigations of COPD have taken place over the last few decades, its pathogenesis is still unclear [2]. No treatment is available to prevent or halt the progression of these disorders [3,4]. We still need to gain deeper insights into their molecular pathogenesis and develop novel therapeutic strategies. Pathologic changes result from intricate molecular network alterations, such as molecular links between subcellular components and disease genes, rather than form a few key genes or other functionally important biomolecules. Based on network thinking, identification of deregulated networks and pathways is an extremely effective discovery approach [5,6]

Methods

Results

Conclusion