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Title: Kinetics and roles of individual TNF receptors in models of acute lung injury in mice
Author: Dorr, Anthony David Peter
ISNI:       0000 0004 2688 7818
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Mechanical ventilation, essential for the support of patients with acute lung injury (ALI), causes exacerbation of the existing pathology, a process termed ventilator-induced lung injury (VILI). The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF) has been consistently implicated in ALI/VILI. TNF activates two receptors, TNFR p55 and p75 that act in opposition during VILI to promote or protect against pulmonary oedema formation, respectively, but the mechanisms underlying this are unknown. Alveolar and plasma soluble TNFR (sTNFR) levels are elevated in ventilated ALI patients and associated with mortality. However, the relevance of these increases is unclear. This project had two main aims: to investigate kinetics and sources of sTNFRs in the alveoli and plasma and investigate mechanisms underlying differential TNFR signalling during VILI, using in vivo mouse models. Investigation of intraalveolar sTNFRs during VILI, and also ALI induced by intratracheal administration of hydrochloric acid or bacterial toxins, showed that intraalveolar sTNFRs are differentially regulated during ALI: VILI/hydrochloric acid induced leakage of sTNFR p55 and p75 from plasma, whereas bacterial toxins induced intraalveolar p75 production. These differences have important implications for TNF signalling and potential use as clinical markers. Investigation of plasma sTNFRs suggests that VILI induces direct production of sTNFRs by the pulmonary vasculature, as opposed to leakage of intraalveolar sTNFRs into the circulation as previously suggested. Development of a flow cytometry technique to study pulmonary TNFR expression was successfully validated using TNFR deficient tissue, but consolidation of data by immunohistochemistry was unsuccessful. Investigation of differential TNFR signalling mechanisms showed that following intratracheal fluid administration, p75 deficient mice exhibit physiological changes consistent with impaired fluid reabsorption, implicating p75 in lung fluid reabsorption during VILI. These data offer new, potentially clinically applicable insights into the involvement of TNFR biology in VILI/ALI and the novel methodologies developed herein constitute useful tools for future research.
Supervisor: Takata, Masao Sponsor: Westminster Medical School Research Trust ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral