D101-10 Breaking Barriers: Characterisation of the Intradermal Lipopolysaccharide Challenge as an In Vivo Model for Controlled Induction of Vascular Leakage in Healthy Volunteers

Rationale 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-centre experimental study evaluated the intradermal lipopolysaccharide challenge model as a tool to induce and characterise vascular leakage in healthy participants. Methods Eight participants (male:female = 4:4) received a total of four id injections of 5 ng lipopolysaccharide in the volar forearms followed by serial pharmacodynamic assessments up to 9 hours after injection. The assessments included laser speckle contrast imaging and multispectral imaging for vasodilation and fluid extravasation. Suction blister induction was performed to assess protein leakage (albumin and total protein), endothelial activation (Olink Explore 384 Cardiometabolic Panel), and neutrophil extravasation (flow cytometry for CD45+/Siglec8+/CD66+ cells). Imaging parameters, protein leakage and neutrophil extravasation were analysed with a mixed-effects model with treatment, time, and treatment*time as fixed effects and subject as random effect using SAS. Least squares means were estimated for each timepoint and tested for statistical significance compared to baseline with a p-value of 0.05 as threshold. The Olink protein expression in blister fluid was evaluated with R software, with boxplots depicting NPX and statistical analysis using the Skillings-Mack test. The statistical significance threshold across all analyses was set at 0.05 and a Benjamini-Hochberg correction was applied to account for multiple testing. Results 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. Conclusion Our findings support the applicability of the id LPS model for 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. This abstract is funded by: CHDR (the scientific institution we work for)