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Title: Accessible biomarkers of inflammatory lung pathophysiology arising from exposure to traffic related particulate matter
Author: Selley, Liza
ISNI:       0000 0004 9350 1882
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Exposure to traffic-related particulate matter (TRPM) is a major cause of pulmonary inflammation, inducing symptoms that range from mild coughing or sore throat to life-threatening asthma attacks or exacerbations of chronic obstructive pulmonary disorder. At present, the molecular mechanisms that underlie pulmonary responses to TRPM in vivo require further characterisation (particularly for those that are stimulated by non-exhaust particulates) but cohort recruitment is hindered by the invasive and uncomfortable nature of sampling via biopsy or bronchial lavage. Extracellular microRNA and metabolite biomarkers offer an attractive alternative measure of responses to TRPM as they are detectable in a number of non-invasively accessible bio-fluids, can be profiled using agnostic, data-driven omics strategies and have been associated with diesel exhaust particle (DEP) exposure in recent studies. Based on evidence that the mechanistic relevance and exploratory power of omics-derived biomarkers can be enhanced through integration of multiple molecular platforms, this study sought to identify miRNA and metabolite biomarkers of pulmonary inflammatory pathways using a combination of microtranscriptomic and metabolomic profiling techniques. Using diverse rodent models of pulmonary inflammation (pharmaceutical, nanoparticle and cytokine-induced), next generation sequencing and microarray analysis identified miR-34b/449a as stimulus-independent, tissue markers of pulmonary specific inflammatory responses. Targeted analyses confirmed the translation of miR-34b/449a over-expression signatures into serum during prototypical (lipopolysaccharide-induced) pulmonary inflammatory responses and into the supernatants of TRPM exposed macrophages in vitro. Meanwhile, 1H nuclear magnetic resonance spectroscopy identified that the miRNA biomarkers were accompanied by changes in the concentrations of energy metabolism substrates, intermediaries and products in both models. The technique also determined that responses to TRPM could be differentiated from lipopolysaccharide-induced responses based on additional changes to extracellular amino acid and myo-inositol content but that no significant differences were made to the biomarker panel where responses to exhaust and non-exhaust particulate exposures were compared. This absence of discriminatory power supported hypothesis-driven characterisations of TRPM-induced toxicity in macrophages. Both DEP and brake abrasion dust (BAD) disrupted mitochondrial membrane potential, inhibited phagocytosis activity and induced cytokine secretion to the same degree. Integrative pathway over-representation analysis (ORA) identified a wide range of cellular pathways that were disrupted in common during prototypical and TRPM-induced pulmonary inflammation. Many of these pathways were eluded to by the metabolite-only ORA but others (such as lipid metabolism and hypoxia signalling pathways) were only detected by the integrative technique. An additional few that belong to characterised responses to TRPM (including glutathione synthesis and xenobiotic metabolism) were excluded by the multi-omics analysis indicated that while the integrative approach enhanced the mechanistic and informative potential of the biomarkers overall, single-omics results were also useful in their own right.
Supervisor: Athersuch, Toby ; Coen, Muireann Sponsor: Medical Research Council ; In Vitro Toxicology Society
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral