OC 19.1 - Rabeprazole is an Agonist of HIF-1 and Promotes Vascular Repair and Resolution of Inflammatory Lung Injury

Background: There are no effective treatments for inflammatory lung injury, including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Severe COVID-19 patients commonly suffer from ARDS. The repositioning of existing drugs is one possible strategy for treatment of ALI/ARDS. We previously showed that vascular repair and resolution of inflammatory lung injury is dependent upon endothelial hypoxia-inducible factor 1 alpha (HIF1a) and forkhead box M1 (FoxM1).

Aims: To identify a candidate agonist of HIF1a/FoxM1 signaling that could effectively treat ALI/ARDS.

Methods: FDA-approved drugs were screened using reporter assays, toxicity assays, and gene expression analyses in vitro. Inflammatory lung injury was assessed in a mouse model of lipopolysaccharide-induced endotoxemia.

Results: We used high throughput screening of a library 1200 FDA-approved drugs, along with hypoxia-response element-driven luciferase reporter assays, cell toxicity assays, and molecular analyses of human lung microvascular endothelial cells, to identify candidate drugs that enhance HIF1 signaling in vitro. One of these drugs, Rabeprazole (Aciphex), caused dose-dependent increases in hypoxia-response element activity without increasing cell death. By treating wild type mice orally with Rabeprazole on 2 consecutive days after sepsis challenge, we were able to identify a dose of Rabeprazole that is well tolerated and enhances vascular repair and resolution of inflammatory lung injury. In timeline studies, we found that Rabeprazole treatment reduces lung vascular leakage, edema, and inflammatory cytokine expression during the repair phrase. We next used conditional knockout mice to show that Rabeprazole increases vascular repair and resolution of inflammatory lung injury through endothelial HIF1a and FoxM1. Rabeprazole-dependent decreases in lung vascular leakage, edema, and inflammatory cytokine expression were completely absent in the conditional HIF1a and FoxM1 knockout mice.

Conclusion(s): Rabeprazole improves murine vascular repair and resolution of sepsis-induced inflammatory lung injury via endothelial HIF1a/FoxM1. This drug represents a promising candidate for repurposing to effectively treat ALI/ARDS.