Asef controls vascular endothelial permeability and barrier recovery in the lung.
Bottom Line: Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability.This effect was lost in Asef(-/-) mice.This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury.
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.Show MeSH
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Mentions: Asef−/− mice and matching Asef+/+ controls were injected with vehicle or HGF before challenge with TRAP6 and mechanical ventilation. Evaluation of the BAL after 4 h of TRAP6/HTV revealed a significant elevation of BAL protein content, reflecting lung barrier dysfunction in both Asef+/+ and Asef−/− mice (Figure 8A). However, HGF-protective effects against TRAP6/HTV-induced increases in BAL protein content observed in Asef+/+ controls were abolished in Asef−/− mice. TRAP6/HTV-induced lung injury caused significant lung vascular leak detected by Evans blue dye accumulation in the lung parenchyma, which was evident in Asef+/+ and Asef−/− mice after 4 h of HTV. In turn, pretreatment with HGF caused a substantial decrease in Evans blue accumulation in Asef+/+ but not Asef−/− mice. Images of original lung preparations showing Evans blue extravasation are shown in Figure 8B. Quantitative analysis of Evans blue–labeled albumin in the lung tissue extracts from these experiments is presented in Figure 8C.
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.