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Tumour necrosis factor-α (TNF) receptor subtype signalling in acute lung injury - a therapeutic approach

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Title: Tumour necrosis factor-α (TNF) receptor subtype signalling in acute lung injury - a therapeutic approach
Authors: Bertok, Szabolcs
Item Type: Thesis or dissertation
Abstract: To date no definite treatment exists for acute lung injury (ALI), only supportive therapy, among which mechanical ventilation is an important tool; however ventilation itself may exacerbate the underlying injury, termed ventilator-induced lung injury (VILI). The pro-inflammatory cytokine tumour necrosis factor alpha (TNF) has been consistently implicated in the pathogenesis of ALI/VILI, however clinical trials with anti-TNF therapy failed to improve the outcome. TNF acts on two cell-surface receptors (TNFRs), p55 and p75, and knock-out studies in ALI/VILI indicate they have directly opposing roles, i.e. promoting or protecting against pulmonary oedema, respectively, but it remains unclear where these signalling mechanisms take place, being the endothelial or epithelial side of the alveolar-capillary membrane. This project had two main aims: to characterise the expression profile and roles of TNF receptor subtypes on each side of the alveolarcapillary membrane and to modulate ALI progression in mouse models by targeting individual TNFRs accordingly. Characterisation studies on freshly harvested mouse pulmonary endothelial cells (PECs) using flow cytometry indicated expression of both receptors with dominance of p55. Knock-out and pharmacological inhibition studies in vivo and in vitro, respectively, found p55 to be the major mediator of TNF-induced adhesion molecule expression on PECs, with a similar but less potent role for p75 that varied across adhesion molecules. Endotoxaemia resulted in rapid shedding of p55 on PECs while expression of p75 was preserved, indicating that the relative role of the receptors may change during inflammatory conditions. Specific inhibition of intraalveolar p55 signalling by domain antibodies significantly attenuated both pulmonary oedema and inflammation in mouse models of VILI and acid-aspiration. These data offer new, potentially clinically applicable insights into the involvement of TNFR biology in ALI and the novel domain antibody technology may open a new therapeutic approach for patients who suffer from, or at risk of ALI.
Content Version: Open Access
Issue Date: Mar-2013
Date Awarded: Mar-2014
URI: http://hdl.handle.net/10044/1/29862
DOI: https://doi.org/10.25560/29862
Supervisor: Takata, Masao
Wilson, Michael
Sponsor/Funder: Wellcome Trust (London, England)
Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Funder's Grant Number: No. 081208
No. D01820X
COLO28224
Department: Department of Surgery and Cancer
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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