IMATINIB: A NOVEL CANDIDATE FOR TREATMENT OF PERMEABILITY EDEMA


Geerten P. van Nieuw Amerongen, Ph.D., VU University Medical Center, Amsterdam, The Netherlands

Endothelial hyperpermeability and vascular leakage are significant pathogenic phenomena. Although contributing to life-threatening conditions like acute respiratory distress syndrome, they currently lack specific therapy. In a case-report we reported fast resolution of pulmonary edema upon treatment with the tyrosine kinase inhibitor imatinib. We tested the hypothesis that imatinib protects against endothelial barrier dysfunction and elucidated how imatinib attenuates edema formation. Imatinib inhibited the thrombin-induced macromolecule passage through human endothelial monolayers, and reduced the maximal drop in trans-endothelial electrical resistance upon thrombin and histamine stimulation. Moreover, imatinib attenuated the thrombin-induced loss of the adherens junction proteins VE-cadherin and beta-catenin. Small interfering RNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-related gene kinase (ARG/Abl2), a previously unknown mediator of endothelial hyperpermeability. Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor, as evidenced by a 2-3 fold increase in CrkL phosphorylation, the downstream target of ARG. The clinical relevance of ARG was confirmed by increased amounts of phosphorylated CrkL in the pulmonary endothelium of septic patients. To test the protective effects of imatinib in vivo, mice were pretreated with imatinib and PAR-1 agonist. Pulmonary vascular permeability was evaluated by measuring the Kfc of isolated perfused mouse lungs. Imatinib pretreated lungs showed a lower Kfc. ARG-deficient mice showed a significant reduction of VEGF-induced vascular leakage. ARG was activated upon endothelial activation in vitro. Finally, we describe treatment of a patient suffering from vascular leak with imatinib in a controlled setting. Thus, we demonstrated that the tyrosine kinase inhibitor imatinib protects against endothelial barrier dysfunction in vitro and in vivo. Imatinib exerts its protective effects via inhibition of ARG/Abl2. These data indicate imatinib may be a novel therapeutic strategy for treatment of endothelial hyperpermeability and lung edema.