Acute respiratory distress syndrome (ARDS) is a major cause of intensive care mortality, with no effective treatment. Despite improvements in patient management in intensive care, ARDS mortality remains high, therefore there is significant unmet need for active therapies. Tumour necrosis factor (TNF) is a major inflammatory cytokine that has long been implicated in ARDS pathology. TNF signals through two related but functionally distinct receptors, TNF receptor 1 and TNF receptor 2 (TNFR1 & TNFR2).
Previous work has shown that signalling through TNFR1 is deleterious in ARDS caused by ventilation and acid aspiration, whereas signalling through TNFR2 is protective. These data suggest that specific inhibition of TNFR1 may be protective in ARDS. In this thesis I investigate the effects of specific TNFR1 inhibition, by a novel TNFR1 domain antibody (dAb™), in two different models of LPS induced ARDS.
Firstly, I showed that TNFR1 inhibition reduces inflammatory cell influx, and macrophage activation when given prior to disease induction. Despite these benefits, physiological parameters remained unaffected. In our second model I combined the LPS stimulus with mechanical ventilation once animals had significant pre-existing injury. Mechanical ventilation is essential for the survival of human ARDS patients, however it can cause iatrogenic ventilator induced lung injury (VILI). In this study I investigated whether specific blockade of intra-alveolar TNFR1 could protect mice with established ARDS from VILI. I showed that administration of the TNFR1 dAb, immediately prior to ventilation, resulted in significant improvements in physiology, alongside significant changes in alveolar macrophage responses. These data provide the first evidence that TNFR1 inhibition can provide protection, in the face of significant pre-existing injury, strongly supporting the further investigation of this approach in the clinic.
While TNF signalling via TNFR1 has been well characterised, the signalling pathways associated with TNFR2 are less clear. In the final section of this thesis I focus on the role of TNFR2 in macrophages, and demonstrate the effects of TNFR2 signalling on TNFR1 pathways as well as identifying some potential TNFR2 specific pathways for the first time.