Exploration of mechanisms of lung injury by TNF receptor signalling
File(s)
Author(s)
Baldi, Rhianna Francesca
Type
Thesis
Abstract
Acute respiratory distress syndrome (ARDS) is a debilitating illness in critical care, with a high mortality rate of around 40%. ARDS is characterised by acute inflammation, hypoxemia and permeability oedema, and treatment is mainly supportive, with the majority of patients requiring invasive mechanical ventilation to maintain gas exchange. However, this can exacerbate injury through ventilator-induced lung injury (VILI) and there remains a significant lack of pharmacological interventions to reduce morbidity and mortality.
Tumour necrosis factor (TNF) is a major pro-inflammatory cytokine which has been implicated in various mechanisms of ARDS pathophysiology. Clinical trials targeting the cytokine itself have been largely unsuccessful, but research has since indicated that specific blockade of TNF receptor 1 (TNFR1) may be protective during lung injury. TNFR1 inhibition has demonstrated benefits in various studies, however the mechanism of protection is unclear and there have been inconsistencies observed across different preclinical models.
This thesis therefore aims to explore mechanisms of lung injury by TNF receptor signalling. We identified a direct impact of TNF on the alveolar epithelium, demonstrating that injurious ventilation induces epithelial dysfunction via TNFR1-dependent apoptotic signalling. However, in a murine model of LPS-induced inflammation, TNF did not exert the same effects. We propose a novel hypothesis whereby microvesicles (MVs) carrying components of the TNFR1-death signalling pathway, such as Fas-associated death domain (FADD), may modulate downstream TNFR1 signalling to enhance apoptosis during VILI. We found that 1hr of injurious ventilation, but not LPS treatment, increases the FADD content in MVs recovered from murine lungs, and demonstrate that treatment of epithelial cells in vitro with TNF and macrophage derived FADD-containing MVs induces cell death.
These findings increase our understanding of the role of TNFR1 signalling in ARDS and VILI and may aid the development of pharmacological interventions to reduce alveolar barrier damage in critical care.
Tumour necrosis factor (TNF) is a major pro-inflammatory cytokine which has been implicated in various mechanisms of ARDS pathophysiology. Clinical trials targeting the cytokine itself have been largely unsuccessful, but research has since indicated that specific blockade of TNF receptor 1 (TNFR1) may be protective during lung injury. TNFR1 inhibition has demonstrated benefits in various studies, however the mechanism of protection is unclear and there have been inconsistencies observed across different preclinical models.
This thesis therefore aims to explore mechanisms of lung injury by TNF receptor signalling. We identified a direct impact of TNF on the alveolar epithelium, demonstrating that injurious ventilation induces epithelial dysfunction via TNFR1-dependent apoptotic signalling. However, in a murine model of LPS-induced inflammation, TNF did not exert the same effects. We propose a novel hypothesis whereby microvesicles (MVs) carrying components of the TNFR1-death signalling pathway, such as Fas-associated death domain (FADD), may modulate downstream TNFR1 signalling to enhance apoptosis during VILI. We found that 1hr of injurious ventilation, but not LPS treatment, increases the FADD content in MVs recovered from murine lungs, and demonstrate that treatment of epithelial cells in vitro with TNF and macrophage derived FADD-containing MVs induces cell death.
These findings increase our understanding of the role of TNFR1 signalling in ARDS and VILI and may aid the development of pharmacological interventions to reduce alveolar barrier damage in critical care.
Version
Open Access
Date Issued
2022-01
Date Awarded
2023-12
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Wilson, Michael
Takata, Masao
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)