DESCRIPTION:ARDS is an acute inflammatory lung disease characterized by hypoxemia and multi-organ failure with mortality reaching 50%. It accounts for almost 200,000 ICU admissions yearly in the US and thus impacts substantially on healthcare cost. Importantly, there are no drugs that treat ARDS. Disease progression is due in part to the dysregulation of the Vascular Endothelial Growth Factor (VEGF). We recently designed a novel short peptide, PR1P, that binds and upregulates endogenous VEGF signaling. Preliminary work from our BBIC Pilot grant showed that inhaled PR1P mitigated acute lung injury (ALI) in an elastase-induced murine emphysema model. We hypothesize that PR1P will be therapeutic in humans with ARDS. The peptide requires proof-of-principle testing in animal and human models. We propose herein Aim 1 to characterize the effect of inhaled PR1P on disease progression in three established murine ARDS models, and in Aim 2 to determine if the therapeutic activity of the peptide is preserved in tissue samples from patients with ARDS. Mice will be treated with inhaled PR1P at different stages of the disease to mimic treatment start times of patients presenting with ARDS. We will characterize the ability of PR1P to mitigate disease severity including 1) lung cell apoptosis and lung 2) inflammation, 3) permeability and 4) damage. Our overall goal is to determine that PR1P mitigates murine ALI and is functional in human tissue samples. If successful, this will provide the proofs of concept necessary to support investment in PR1P for use in humans with ARDS.