INTRODUCTION: Liberal administration of supplemental oxygen (O METHODS AND ANALYSIS: We hypothesise that (1) short-term exposure to hyperoxia will induce mild pulmonary inflammation and cellular injury and that (2) hyperoxia will accentuate pulmonary inflammation and cellular injury in the setting of inhaled lipopolysaccharide challenge. To test our hypotheses, we will conduct a randomised, double-blind, placebo-controlled study of hyperoxia administered via a high-flow nasal O ETHICS AND DISSEMINATION: Dissemination of the research findings will be achieved in the following ways: (1) Our findings will be presented at national and international meetings with open-access abstracts online and (2) in accordance with the open-access policies proposed by the leading research funding bodies we aim to publish the findings in high quality peer-reviewed open-access journals. TRIAL REGISTRATION NUMBER: NCT05414370.