The roles of tumour necrosis factor and its receptors in the injury, inflammation and resolution of acute lung injury

Abstract

The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care. Despite improvements in intensive care and advances in respiratory support, mortality remains high with no active treatments. Tumour necrosis factor (TNF) is a cytokine that has been implicated in ARDS for over 30 years but its precise roles remain elusive. It signals through two main receptors – the p55 TNF receptor and p75 TNF receptor. The first aspect of this thesis investigated the roles of TNF receptors (TNFR) in the early phase of acute acid-induced lung injury. Using genetically modified mice we discovered that alveolar oedema, as a result of acid aspiration, was specifically mediated through the p55-TNFR, whereas, the p75-TNFR promoted a protective effect. Alveolar oedema formation occurred through an effect independent to the downstream inflammatory events, but instead through the activation of TNF/p55-TNFR/caspase-8 death signalling specifically in the alveolar epithelium. Furthermore, this death-signalling axis led to a reduced alveolar epithelial fluid clearance rate. Epithelial dysfunction occurred prior to epithelial cell death and pharmacological blockade of caspase-8 rescued epithelial function with improvements in gas exchange, suggesting that the activation of caspase-8 per se induced this functional deficit in the alveolar epithelium. The second part of the thesis describes the development of a longer-term model of acid aspiration aimed at extending investigation into the later, arguably more clinically relevant, phases of lung injury (0-10 days). Mice showed respiratory physiology that reached clinical ARDS criteria with significant inflammation and epithelial/endothelial injury, which importantly, resolved facilitating investigation into reparative processes. This model was further characterised using novel flow cytometry protocols to examine the compartmental location of leukocytes during the various phases of ARDS. This model provides a translational platform to allow investigation into the injurious, inflammatory, and resolution mechanisms of ARDS.Open Acces