Metabolomics in asthma: A platform for discovery

Abstract

Asthma, characterized by airway hyperresponsiveness, inflammation and remodeling, is a chronic airway disease with complex etiology. Severe asthma is characterized by frequent exacerbations and poor therapeutic response to conventional asthma therapy. A clear understanding of cellular and molecular mechanisms of asthma is critical for the discovery of novel targets for optimal therapeutic control of asthma. Metabolomics is emerging as a powerful tool to elucidate novel disease mechanisms in a variety of diseases. In this review, we summarize the current status of knowledge in asthma metabolomics at systemic and cellular levels. The findings demonstrate that various metabolic pathways, related to energy metabolism, macromolecular biosynthesis and redox signaling, are differentially modulated in asthma. Airway smooth muscle cell plays pivotal roles in asthma by contributing to airway hyperreactivity, inflammatory mediator release and remodeling. We posit that metabolomic profiling of airway structural cells, including airway smooth muscle cells, will shed light on molecular mechanisms of asthma and airway hyperresponsiveness and help identify novel therapeutic targets.

Keywords: Airway smooth muscle; Asthma; Big data; Metabolism.

Fig. 1.. Workflow of metabolomics-based asthma study

A typical metabolomic workflow in asthma involves either targeted metabolomics to test a hypothesis or untargeted metabolomics approach to generate testable hypotheses. In targeted approach, quantitative comparison of pre-selected metabolites leads to identifying profiles related to disease states or treatment conditions. In the untargeted approach, disease or treatment-associated profiles can still be elucidated, however, bench validation is critical for testing hypotheses. The end result of both approaches is to identify disease-selective diagnostic biomarkers and understanding novel mechanisms of disease, which potentially lead to novel therapeutic targets. NMR – Nuclear Magnetic Resonance, LC-MS – Liquid Chromatography – Mass Spectrometry, HPLC-MS – High-Performance Liquid Chromatography – Mass Spectrometry, KEGG – Kyoto Encyclopedia of Genes and Genomes, HMDB – Human Metabolome Database, MassBank – MassBank Europe Spectral Database, OpenMS – Open-source software for mass spectrometry.

Fig. 2.. Cell types and their metabolic roles in asthma

Each tissue in lungs plays its unique role in asthma pathology. Each tissue is composed of differentiated cell types, homogeneous or heterogeneous, with critical functions. In these cells, altered mitochondrial functions and metabolism of macro- and micro-nutrients -elaborated in the main text- modulate the specialized cellular functions. Airway smooth muscle (ASM) cells primarily dirve bronchial spasm in asthma, which is charaterized by increased cytosolic Ca²⁺ and myosin light chain (MLC) phosphorylation. Asthma is characterized by airway inflammtion, remodeling, and hyperresponsiveness. DC - dendritric cells, T_reg - regulatory T-lymphocytes, Ca²⁺ - cytosolic Ca²⁺, pMLC - phosphorylated myosin light chain.