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

Abstract

Endothelial dysfunction underlies the pathophysiology of vascular disorders such as acute lung injury (ALI) syndromes. Recent work has identified the Abl family kinases (c-Abl and Arg) as important regulators of endothelial cell (EC) barrier function and suggests that their inhibition by currently available pharmaceutical agents such as imatinib may be EC protective. Here we describe novel and differential effects of imatinib in regulating lung pathophysiology in two clinically relevant experimental models of ALI. Imatinib attenuates endotoxin (LPS)-induced vascular leak and lung inflammation in mice but exacerbates these features in a mouse model of ventilator-induced lung injury (VILI). We next explored these discrepant observations in vitro through investigation of the roles for Abl kinases in cultured lung EC. Imatinib attenuates LPS-induced lung EC permeability, restores VE-cadherin junctions, and reduces inflammation by suppressing VCAM-1 expression and inflammatory cytokine (IL-8 and IL-6) secretion. Conversely, in EC exposed to pathological 18% cyclic stretch (CS) (in vitro model of VILI), imatinib decreases VE-cadherin expression, disrupts cell-cell junctions, and increases IL-8 levels. Downregulation of c-Abl expression with siRNA attenuates LPS-induced VCAM-1 expression, whereas specific reduction of Arg reduces VE-cadherin expression in 18% CS-challenged ECs to mimic the imatinib effects. In summary, imatinib exhibits pulmonary barrier-protective and antiinflammatory effects in LPS-injured mice and lung EC; however, imatinib exacerbates VILI as well as dysfunction in 18% CS-EC. These findings identify the Abl family kinases as important modulators of EC function and potential therapeutic targets in lung injury syndromes.

Targeting Abl Kinases to Regulate Vascular Leak During Sepsis and Acute Respiratory Distress Syndrome

“…These potent barrier protective effects, in response to several barrier disruptive agonists, strongly support the hypothesis that Abl kinases are central mediators of vascular integrity. This work is supported by in vivo studies that demonstrate a protective effect of imatinib in vascular leak induced by injection of VEGF (intradermal), thrombin receptor activating peptide (TRAP) (intravenous, IV), and LPS (intratracheal, IT), and the cecal ligation and puncture (CLP) sepsis model 9–12 . Additionally, imatinib restores blood-brain-barrier (BBB) integrity and decreases intracerebral hemorrhage in murine models 37, 38 .…”

“…Although the mechanisms are not completely understood, they include increased Rac1/Rap1 activity and decreased Ca 2+ mobilization, non-muscle MLCK (nmMLCK) activation, and stress fiber formation 11 . Additionally, vascular barrier disruption induced by both LPS and oxidative stress are attenuated by imatinib treatment 12, 13 . These potent barrier protective effects, in response to several barrier disruptive agonists, strongly support the hypothesis that Abl kinases are central mediators of vascular integrity.…”

“…In contrast with these barrier protective effects, Abl kinase inhibition worsens endothelial barrier disruption in EC challenged with 18% cyclic stretch, and worsens vascular leak in a murine model of ventilator-induced lung injury (VILI) induced by high tidal volume mechanical ventilation (MV) 12 . These observations indicate differential pathophysiology of VILI and ARDS due to other causes 39 and suggest that Abl kinase inhibition in ARDS patients undergoing MV should be approached with caution.…”

“…Imatinib attenuates LPS-induced VCAM-1 expression and inflammatory cytokine (IL-6, and IL-8) production in human pulmonary artery EC (HPAEC), and these effects are mimicked by silencing of c-Abl, but not Arg 12 . Our unpublished data indicate that imatinib prevents LPS-induced NFκB phosphorylation and nuclear translocation in HPAEC, suggesting that LPS increases VCAM expression and cytokine production via a c-Abl/NFκB dependent signaling pathway.…”

Claudins: Gatekeepers of lung epithelial function

“…However, imatinib treated mice have a complex response to lung injury in that they are protected from endotoxin induced lung injury but have an increased sensitivity to VILI [135]. Although the mechanism underlying this divergence in response is not known at present, we speculate that this is due to differential regulation of the endothelial and epithelial parts of the alveolar barrier.…”