Inhalation injury can lead to pulmonary complications resulting in the development of respiratory distress and severe hypoxia. Respiratory distress is one of the major causes of death in critically ill patients with a reported mortality rate of up to 45%. The present study focuses on the effect of oxygen microbubble (OMB) infusion via the colon in a porcine model of smoke inhalation-induced lung injury. Juvenile female Duroc pigs (n= 6 colonic OMB,n= 6 no treatment) ranging from 39 to 51 kg in weight were exposed to smoke under general anesthesia for 2 h. Animals developed severe hypoxia 48 h after smoke inhalation as reflected by reduction in SpO2to 66.3 ± 13.1% and PaO2to 45.3 ± 7.6 mmHg, as well as bilateral diffuse infiltrates demonstrated on chest X-ray. Colonic OMB infusion (75–100 mL/kg dose) resulted in significant improvements in systemic oxygenation as demonstrated by an increase in PaO2of 13.2 ± 4.7 mmHg and SpO2of 15.2 ± 10.0% out to 2.5 h, compared to no-treatment control animals that experienced a decline in PaO2of 8.2 ± 7.9 mmHg and SpO2of 12.9 ± 18.7% over the same timeframe. Likewise, colonic OMB decreased PaCO2and PmvCO2by 19.7 ± 7.6 mmHg and 7.6 ± 6.7 mmHg, respectively, compared to controls that experienced increases in PaCO2and PmvCO2of 17.9 ± 11.7 mmHg and 18.3 ± 11.2 mmHg. We conclude that colonic delivery of OMB therapy has potential to treat patients experiencing severe hypoxemic respiratory failure.