METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial (HMVEC-L) cells and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised, controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin.
RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro, and also significantly attenuated inflammation and signs of lung injury in non-human primates. In a randomized, placebo-controlled trial of nebulised GSK1995057 in healthy humans challenged with a low-dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release and signs of endothelial injury in bronchoalveolar lavage and serum samples.
CONCLUSION: Pulmonary delivery of a selective TNFR1 dAb antagonist may offer a novel therapeutic approach to the prevention or treatment of acute respiratory distress syndrome (ARDS).
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- School of Medicine, Dentistry and Biomedical Sciences - Clinical Professor
- Wellcome Wolfson Institute for Experimental Medicine