Breaking Barriers: Characterization of the Intradermal Lipopolysaccharide Challenge as an <i>In Vivo</i> Model for Controlled Induction of Vascular Leakage in Healthy Volunteers

Vascular leakage and its associated phenomena vasodilation and endothelial activation are pathophysiological features of various diseases. Multiple drug candidates targeting these phenomena are in development, necessitating translational models to demonstrate proof‐of‐pharmacology and proof‐of‐mechanism in early‐phase clinical trials. This single‐center experimental study evaluated the intradermal lipopolysaccharide (id LPS) challenge model as a tool to induce and characterize vascular leakage in healthy participants. Eight participants (male:female = 4:4) received id LPS in the volar forearms, followed by serial pharmacodynamic assessments, including imaging and suction blister induction up to 9 hours after injection. Id LPS administration resulted in significant increases in skin perfusion ( P  < 0.0001), erythema ( P  = 0.0013), and skin volume ( P  = 0.0008), indicating initial stages of inflammation and fluid extravasation. Blister fluid analysis revealed elevated extravascular concentrations of albumin ( P  = 0.0011), total protein ( P  < 0.0001), and neutrophils ( P  = 0.0342), supporting the presence of vascular leakage. Moreover, the expression of endothelial activation markers VCAM‐1 ( P  = 0.0015), ICAM‐1 ( P  = 0.0004), ITGB1 ( P  = 0.01), and E‐selectin ( P  = 0.0218) increased significantly. Disruption of endothelial cell–cell integrity was supported by increased expression of VE‐cadherin ( P  = 0.0002) in blister fluid. These findings support the applicability of the id LPS model for the induction of vascular leakage in humans. This model holds potential as a translational tool for evaluating the pharmacodynamic responses of vascular leakage‐targeting drugs in early clinical development.