PROJECT SUMMARY/ABSTRACT: Mortality from sepsis and the acute respiratory distress syndrome (ARDS) remain unacceptably high despite advances in critical care. Carbon monoxide (CO) is a novel therapeutic for ARDS supported by compelling data from experimental models of sepsis and acute lung injury (ALI). We have demonstrated that low dose CO confers protection in cell culture and animal models of sepsis and ALI. We have shown that CO suppresses mitochondrial dysfunction and inflammasome activation, activates mitochondrial biogenesis, and accelerates resolution of inflammation via biosynthesis of specialized pro-resolving mediators (SPM), making CO a highly promising therapy for treatment of sepsis and ARDS. We have developed and tested a ventilator-compatible CO Delivery System and a CO dosing strategy in a non-human primate model of pneumonia-induced ALI. We demonstrated that low dose inhaled CO (iCO) can be safely administered to mechanically ventilated baboons with sepsis and ALI, and that the rise in carboxyhemoglobin (COHb) can be accurately predicted using the Coburn-Forster-Kane (CFK) equation. We recently completed a fixed dose Phase Ia trial of iCO in patients with sepsis-induced ARDS, which showed that precise delivery of low dose iCO is feasible and safe in mechanically ventilated ARDS patients. We showed that the CFK equation is highly accurate at predicting COHb levels, suggesting that the CFK equation can be used to individually titrate iCO dosing to ensure consistent and safe systemic uptake in ARDS patients with varying degrees of impaired gas exchange. We now propose a Phase Ib trial to evaluate a personalized medicine approach to iCO dosing and to examine functional biological signatures underlying the beneficial effects of iCO in sepsis-induced ARDS. In Aim 1, we will conduct a randomized, double-blind, placebo-controlled Phase Ib trial to evaluate the safety and accuracy of a CFK equation-based personalized iCO dosing algorithm in mechanically ventilated patients with sepsis-induced ARDS. For our primary endpoint, we will evaluate safety and the accuracy of our precision medicine approach to achieve a target COHb level of 6-8%. In Aim 2, we will examine the impact of personalized iCO therapy on biological signatures of mitochondrial dysfunction, inflammasome activation, necroptosis, and resolution of inflammation in patients with sepsis-induced ARDS. We will measure levels of mitochondrial DNA, inflammasome-regulated cytokine IL-18, necroptosis regulator RIPK3, and SPMs in plasma and bronchoalveolar lavage fluid in iCO- and placebo-treated subjects to determine whether CO modulates these pathways. We will examine whether modulation of these novel pathways correlates with plasma COHb levels and clinical outcomes in the Phase Ib trial. At the completion of this study, we will be well-poised to conduct a Phase IIb trial to evaluate the efficacy of precision-based low dose iCO therapy in patients with sepsis-induced ARDS.