Abstract 122: Rabeprazole Enhances Vascular Repair And Resolution Of Sepsis-induced Lung Injury Through HIF1/FoxM1 Signaling

Abstract

Objective: There are currently no effective treatments for sepsis-induced inflammatory lung injury, including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The repositioning of existing drugs is one possible strategy for the treatment of ALI/ARDS. We previously showed that vascular repair and resolution of ALI is dependent upon hypoxia-inducible factor 1 alpha (HIF1a) and forkhead box M1 (FoxM1) in endothelial cells. The aim of this study was to identify a candidate agonist of HIF1a/FoxM1 signaling to treat ALI/ARDS. Approach and Results: First, we adopted a high throughput screening approach of a library of 1200 FDA-approved drugs by using hypoxia response element (HRE)-driven luciferase reporter assays, cell toxicity assays, and molecular analyses of human lung endothelial cells, to identify candidate HIF1 agonists in vitro . One of the top candidate drugs, Rabeprazole (also known as Aciphex), gave rise to dose-dependent increases in HRE luciferase activity without concurrent increases in cell death. Next, we performed dose-response studies of Rabeprazole in a mouse model of sepsis-induced ALI. By treating wild type mice orally with Rabeprazole on 2 consecutive days after endotoxic sepsis challenge, we were able to identify a dose of Rabeprazole that is well tolerated and enhanced vascular repair and resolution of ALI. In timeline studies of murine inflammatory lung injury, we found that Rabeprazole treatment resulted in reductions in lung vascular leakage, edema, and inflammatory cytokine expression during the repair phrase following sepsis-induced ALI. Finally, we used conditional knockout mice to show that Rabeprazole increases vascular repair and resolution of ALI via HIF1a/FoxM1 signaling. Conclusions: Rabeprazole is a HIF1a agonist that improves vascular repair and resolution of sepsis-induced inflammatory lung injury. Rabeprazole represents a promising candidate for repurposing to treat ALI/ARDS.