Metabolomics Investigation Reveals Metabolite Mediators Associated with Acute Lung Injury and Repair in a Murine Model of Influenza Pneumonia.

Choon Nam Ong,Yadunanda Kumar,Tze Khee Chan,Jian Zhu Chen,Yie Hou Lee,Wanxing Eugene Ho,Dahai Zheng,Liang Cui,Steven R Tannenbaum

doi:10.1038/srep26076

Abstract

Influenza virus infection (IVI) can cause primary viral pneumonia, which may progress to acute lung injury (ALI) and respiratory failure with a potentially fatal outcome. At present, the interactions between host and influenza virus at molecular levels and the underlying mechanisms that give rise to IVI-induced ALI are poorly understood. We conducted a comprehensive mass spectrometry-based metabolic profiling of serum, lung tissue and bronchoalveolar lavage fluid (BALF) from a non-lethal mouse model with influenza A virus at 0, 6, 10, 14, 21 and 28 days post infection (dpi), representing the major stages of IVI. Distinct metabolite signatures were observed in mice sera, lung tissues and BALF, indicating the molecular differences between systematic and localized host responses to IVI. More than 100 differential metabolites were captured in mice sera, lung tissues and BALF, including purines, pyrimidines, acylcarnitines, fatty acids, amino acids, glucocorticoids, sphingolipids, phospholipids, etc. Many of these metabolites belonged to pulmonary surfactants, indicating IVI-induced aberrations of the pulmonary surfactant system might play an important role in the etiology of respiratory failure and repair. Our findings revealed dynamic host responses to IVI and various metabolic pathways linked to disease progression, and provided mechanistic insights into IVI-induced ALI and repair process.

Highlights

While the most common symptoms of Influenza virus infection (IVI) include fever, runny nose, sore throat, cough and fatigue, susceptible populations can have a variety of more severe complications including primary viral pneumonia, which can progress to acute lung injury (ALI) and respiratory failure with a potentially fatal outcome[3]
Given the critical roles played by surfactants in maintaining pulmonary biology[14], it is tempting to speculate that specific bronchoalveolar lavage fluid (BALF) metabolites may be perturbed and restored over the course of IVI-induced ALI
We described the dynamics of host responses to IVI, and laid out the temporal changes occurring within the metabolic pathways, observing distinct metabolome changes in serum, lung and BALF indicative of the differences between systematic and localized host responses to IVI

Summary

Introduction

While the most common symptoms of IVI include fever, runny nose, sore throat, cough and fatigue, susceptible populations can have a variety of more severe complications including primary viral pneumonia, which can progress to acute lung injury (ALI) and respiratory failure with a potentially fatal outcome[3]. Macrophages are recruited to the infected lung and can induce alveolar epithelial cell apoptosis damage and lung injury by expressing tumor necrosis factor-related apoptosis-inducing ligand in severe IVI6,7. Given the critical roles played by surfactants in maintaining pulmonary biology[14], it is tempting to speculate that specific bronchoalveolar lavage fluid (BALF) metabolites may be perturbed and restored over the course of IVI-induced ALI. We systematically characterized cytokines, proteome, and markers of macrophage and neutrophil activities in serum and BALF of a non-lethal murine influenza pneumonia model with infection-induced ALI25. We employed global metabolomics analyses of sera, lung tissues and BALF in this established non-lethal influenza murine model, with the aim of identifying key metabolic pathways linked to disease progression and understanding the molecular mechanisms of IVI-induced aberrations of the pulmonary surfactant system during ALI. The mechanisms leading to these metabolic changes were explored

Methods

Results

Conclusion