Wellcome Trust PhD Programme for Clinicians at Imperial College London. (360G-Wellcome-092851_Z_10_Z)

Aspiration pneumonitis (AP) has significant morbidity and mortality in various clinical settings within hospital medicine. Manifestations vary from mild sub-clinical aspiration to severe acute respiratory distress syndrome, but all aspiration events predispose to pneumonia. Using a genetic approach, we found that, in the early phases of mouse AP, tumour necrosis factor-alpha (TNF) has critical and opposing effects on pulmonary oedema formation, depending on which of its two receptors it signals through. We therefore hypothesise that during the entire course of AP (a model of sterile acute lung injury), TNF receptor I (TNFR1) mediates deleterious pro-inflammatory effects, whereas TNF receptor II (TNFR2) mediates anti-inflammatory/pro-resolving effects. We aim to investigate the mechanisms by which TNFR signaling influences the progression and resolution of AP, focusing on three key lung injury paradigms: a. Alveolar oedema development and fluid clearance mechanisms. b. Intra-alveolar coagulation and resolution through fibrinolysis. c. Alveolar macrophage phenotype and function ? pro-inflammatory vs pro-resolving. The potential therapeutic impact whereby manipulation through specific inhibition of the TNFR1 and/or activation of the TNFR2 may attenuate injury in acute pulmonary syndromes is enormous.