Late Breaking Abstract - Endothelial Cell-Specific Anticoagulation Reduces Inflammation in a Mouse Model of ALI

Abstract

Background: Tissue Factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI), but to date no anti-inflammatory therapy with local targeted coagulation inhibitors has been tested. Objective: To explore whether targeted anticoagulant fusion proteins can protect lipopolysaccharide (LPS)-induced ALI，and to investigate a novel therapeutic strategy for treatment against ALI. Methods: We used two strains of transgenic (Tg) mice expressing respectively human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31–positive cells, including vascular endothelial cells (EC). The expression of chemokines and proinflammatory cytokines in mice lungs were examined after 24 hours interfered with LPS, alongside the extent of leukocyte infiltration and overall survival rate. Results: Expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the level of proinflammatory cytokines, and promoted survival after LPS-induced ALI. These outcomes were associated with inhibition of the expression of chemokine CCL2. By prior engraftment of the Tg strains with WT bone marrow, it was confirmed that the changes seen were a specific effect of transgene expression by EC. Conclusion: Our data indicate that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data significantly enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment.