= Emerging. More than 5 years before clinical availability. (16.60%, 2024)
= Expected to be clinically available in 1 to 4 years. (37.02%, 2024)
= Clinically available now. (46.38%, 2024)
MSACL 2024 : Want

MSACL 2024 Abstract

Self-Classified Topic Area(s): Other -omics > Metabolomics

Podium Presentation in Steinbeck 3 on Wednesday at 16:05 (Chair: Tim Garrett / Angela Kruse)

Understanding the Development of Pain Due to Tissue Injury Through Novel Metabolic Changes

Elizabeth Want, Joshua Cuddihy, Dominic Friston, Istvan Nagy
Imperial College, London, UK

Elizabeth Want, PhD (Presenter)
Imperial College London

Presenter Bio: I am a Senior Lecturer in Molecular Spectroscopy in the Department of Metabolism, Digestion and Reproduction. I joined Imperial College in 2006 after working as a postdoctoral researcher at the Scripps Research Institute in La Jolla, CA. At Imperial College, I was initially a postdoctoral researcher for the Consortium for Metabonomic Toxicology (COMET) group.

My research focuses primarily on the development and application of novel mass spectrometry (MS) based techniques for metabolic phenotyping and on the fusion of mass spectrometric methods with chemometric analysis, which is currently a significant bottleneck in the analysis pipeline. Broadly, my research at Imperial College has involved the development, optimisation and application of UPLC-MS methodologies for the analysis of biological samples, largely in the context of metabolic phenotyping: serum, urine, tissue, amniotic fluid, and microdialysates. These developmental advances have resulted in shorter analysis times – and therefore higher sample throughput – key for large scale metabolic phenotyping studies. Peak detection and analytical reproducibility have been enhanced, improving metabolome coverage and the potential for biomarker identification and quantification.

I am applying these methods to biomedical research areas including toxicology, cardiovascular disease, neonatal disease and development, maternal exposures and effects on early childhood, and neurological diseases.


INTRODUCTION: Tissue injury, including burns, are a major trauma affecting millions worldwide every year. These injuries cause death and morbidity, resulting in huge healthcare costs and impacting both patients and their families. After injury, intracellular molecules are released, triggering inflammatory reactions to restore tissue function and resulting in persistent pain. This pain can persist for months or years after the injury itself, affecting quality of life. However, these pain-inducing molecules are largely unidentified, hampering understanding of tissue injuries and the ability to treat them effectively.

OBJECTIVES: Using a mass spectrometry-based workflow, we aim to improve understanding of molecular changes during tissue injury, to advance treatment of tissue injuries, reduce pain and improve patient outcomes.

METHODS: We have developed a scalding burn injury model and metabolomics workflow for analysing dermal microdialysate and skin from burn-injured and control subjects. The burn injury model facilitates collection of samples immediately after injury (minutes) and enables molecular changes to be followed over time, while clinical samples provide insight into longer term metabolic changes (days). We combined ultra-performance liquid chromatography (UPLC) and desorption electrospray ionisation (DESI) imaging mass spectrometry to elucidate metabolite and lipid changes after burn injury. For metabolite and lipid profiling, microdialysate and skin samples from burned and non-burned subjects were extracted and subjected to reversed-phase chromatography employing in-house methods, using a UPLC Acquity system coupled to a Synapt G2-S mass spectrometer. DESI-MS imaging was performed on sections of burned and non-burned skin from patients (n=72) in positive and negative ion mode using a Waters Xevo G2 QTOF instrument. Data were pre-processed as required and further analysed using univariate and multivariate approaches to identify significant molecular alterations due to burn injury.

RESULTS: Metabolic changes were observed in response to burn injury, including elevated uric acid and niacinamide, known to be involved in tissue repair and wound healing. A novel and significant finding was that lysophosphatidylcholine (LPC) species were significantly altered in both microdialysate and skin. Of specific interest were 14:0, 16:0 and 18:0-LPCs, all elevated following burn injury, due to oxidative stress. These pro-inflammatory lipids can be hydrolysed to lysophosphatidic acid, which causes pain through demyelination and activation of pain-related molecules on primary sensory neurons. DESI-MS showed significant alterations in skin lipid content 5-9 days after scalding burn injury, also revealing the increase in 18:0-LPC to be in the upper and middle third of the dermis. RNAseq data indicated several LPC metabolic enzymes to be differentially expressed after burn injury. Subsequent in vitro and in vivo studies revealed that administration of 18:0-LPC induced immediate pain and development of hypersensitivities to mechanical and heat stimuli, through the modification of specific ion channels.

CONCLUSION: Burn injury causes significant and consistent alterations in small molecules and lipids, in both microdialysate and skin samples. Importantly, 18:0-LPC was observed to contribute to the development and persistence of pain. These lipids have also been found to increase in other tissue injuries (e.g. ischemia, surgical injuries), and contribute to the development of inflammation, insulin resistance, and atheroschlerotic plaques. Therefore, increased 18:0 LPC likely to be an important mechanism for the development of hypersensitivities in tissue injuries. These novel findings could potentially improve patient care and outcomes by reducing pain and inflammation and providing better treatments.

Financial Disclosure

Board MemberyesMSACL EU, help with abstracts etc on MSACL US
IP Royaltyno

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