Effective Treatment of Edema and Endothelial Barrier Dysfunction With Imatinib

Abstract

Background-Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case report, we described fast resolution of pulmonary edema on treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation. Methods and Results-We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro-and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. 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 barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extracellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against vascular endothelial growth factor-induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis, imatinib treatment (6 hours and 18 hours after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24 hours after induction of sepsis). Conclusions-Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema and indicate Arg as novel target for edema treatment. (Circulation. 2012;126:2728-2738.)

Differential and opposing effects of imatinib on LPS- and ventilator-induced lung injury

“…Previous studies also have revealed barrier-protective effects of imatinib. Imatinib attenuated endothelial barrier disruption induced by thrombin or histamine in vitro and VEGF or murine sepsis (2). Another study demonstrated the capability of imatinib to inhibit endothelial permeability induced by the inflammatory agents VEGF, thrombin, and histamine in human microvascular EC (11).…”

“…Recent studies have demonstrated that the chemotherapeutic drug imatinib, an inhibitor of the Abl family of tyrosine kinases as well as several other enzymes, has both vascular barrier-protective and anti-inflammatory properties (2,61). These intriguing observations suggest that imatinib may be a promising therapeutic strategy for ALI syndromes.…”

“…These kinases are involved in a variety of cytoskeleton processes, regulate cellcell adhesion (9,29,49,63), and recently have emerged as important mediators of endothelial function in a stimulusdependent manner. Specifically, we previously reported that c-Abl mediates the EC cytoskeletal rearrangements that are critical for enhanced barrier integrity after S1P, a barrierprotective sphingolipid, and the pharmaceutical agent FTY720 (20,59) In contrast to this barrier-enhancing role, c-Abl also mediates H 2 O 2 -induced disruption of rat lung microvascular endothelium (58), but not thrombin-induced human EC permeability, which is specifically dependent on Arg expression (2). From these studies, it is clear that c-Abl and Arg regulate EC barrier function in a stimulus-specific manner despite their structural and functional similarities.…”

“…We previously reported that c-Abl mediates enhancement of the lung EC barrier by the potent agonists S1P or FTY720 (20,59). In contrast, other reports indicate that c-Abl mediates oxidative stress-induced hyperpermeability (57,58), whereas Arg mediates EC barrier disruption induced by thrombin or VEGF (2). Additional studies support both similar and distinct roles for c-Abl and Arg kinases in other cellular processes relevant to barrier function including focal adhesion and cytoskeletal dynamics (48,62).…”

“…Previous studies have suggested differential roles for the Abl family kinases, c-Abl and Arg, in mediating EC barrier function (2,11). Because imatinib inhibits both these kinases, siRNA technology was employed to individually downregulate the expression of c-Abl or Arg in HPAEC to investigate the specific functions of c-Abl and Arg in our models of EC dysfunction.…”