Background
In 2008 Overbeek et al. reported a patient who demonstrated very fast recovery of pulmonary edema upon initiation of imatinib therapy. This patient was admitted for pulmonary hypertension (based on pulmonary veno-occlusive disease), but had severe respiratory impairment, among others due to concomitant pulmonary edema. Upon initiation of imatinib for the pulmonary hypertension (Schermuly 2005, Hoeper 2013), rapid recovery of respiratory status and reversal of edema was observed. Due to the very fast effect, a direct effect of imatinib on pulmonary endothelial barrier function was hypothesized (Overbeek 2008). This hypothesis was evaluated in subsequent preclinical in vitro and in vivo studies.
Imatinib is a small molecule inhibitor that is well known for its ability to block the ATPase activity of various kinase enzymes, including c-Abl, Abl-related gene (ARG), PDGFR, DDR-1 and c-KIT. c-Abl is a proto-oncogene, on fusion of which with bcr results in a chimeric Bcr-Abl protein with activated Abl tyrosine kinase activity (Lugo 1990), the underlying cause of CML (Schiffer 2007; Druker 2001).
Using in vitro measures of endothelial permeability, Aman et al (2012) demonstrated that imatinib preserves endothelial barrier integrity during stimulation with inflammatory stimuli. The effect was demonstrated in primary human endothelial cells from various origins (umbilical vein, pulmonary microvasculature, and skin microvasculature) and with various inflammatory stimuli (thrombin, histamine, vascular endothelial growth factor (VEGF)). These effects were observed with imatinib concentrations that parallel plasma concentrations measured in CML patients receiving imatinib. A range of preclinical evidence indicates that imatinib protects endothelial barrier function via the inhibition of Abl-related gene (ARG) (Aman et al, patent WO2012150857 A1). Knockdown of ARG using ARG siRNA in this in vitro model significantly reduced thrombin-induced hyper-permeability, with a similar profile of effects on electrical resistance and permeability, compared to imatinib treatment.
The protective effect of imatinib on the endothelial barrier has been confirmed using in vivo models of vascular leak. Pretreatment of mice with imatinib reduced VEGF-induced vascular leak in skin. Similarly, imatinib attenuated vascular leak in an ex vivo model of pulmonary vascular permeability. The relevance of imatinib treatment to disease states was demonstrated in a sepsis model, in which it reduced inflammatory vascular leak in both the kidneys and lungs. Of note, imatinib in these mice was initiated 6 hours after induction of sepsis (Aman 2012).
Together, this preclinical work indicates that imatinib effectively protects the pulmonary endothelial barrier during inflammation, both in human microvascular lung endothelial cells, and in murine models of pulmonary vascular leak and systemic inflammation. As inflammatory disruption of the endothelial barrier is a key pathophysiological mechanism in the development of ARDS, these data strongly support application of imatinib in ARDS. The protective effect of imatinib was confirmed in several other preclinical studies, which also demonstrated that imatinib reduced pulmonary vascular leak, improved oxygenation and reduced mortality in various mouse models of acute lung injury (Stephens et al, 2014; Letsiou, 2015).
In vitro studies |
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Model |
Effect of imatinib |
Reference |
Rat aortic endothelial cells |
Protects endothelial barrier |
Kurimoto et al, Am J Physiol Heart Circ Physiol 2004 Link |
Human umbilical vein endothelial cells |
Protects endothelial barrier, improves cell-matrix adhesion |
Aman et al, Circ 2012 Link |
Human lung microvascular endothelial cells |
Protects endothelial barrier |
Aman et al, Circ 2012 Link |
Immortalized endothelial cells |
Protects endothelial barrier |
Chislock et al, PLoS One 2013 Link |
Human umbilical vein endothelial cells |
Protects endothelial barrier |
Kim et al, ATVB 2014 Link |
Mouse lung microvascular endothelial cells |
Protects endothelial barrier |
Stephens et al, Am J Physiol 2014 Link |
In vivo studies |
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Model |
Effect of imatinib |
Reference |
Bleomycin-induced lung injury |
Anti-inflammatory; anti-fibrotic |
Rhee et al, Respiration 2011 Link |
Isolated perfused lung model (mouse) |
Inhibits lung vascular leak |
Aman et al, Circ 2012 Link |
Miles assay (mouse) |
Attenuates vascular leak in skin |
Aman et al, Circ 2012 Link |
Cecal Ligation & Puncture (Sepsis) (mouse) |
Attenuates vascular leak in lungs, kidneys |
Aman et al, Circ 2012 Link |
Intratracheal LPS (mouse) |
Attenuates pulmonary edema |
Kim et al, Crit Care 2013 Link |
Ischemia-reperfusion in reperfusion lung |
Reduces endothelial cytotoxicity |
Stephens et al, Am J Physiol 2014 Link |
Miles assay (mouse) |
Attenuates vascular leak in skin |
Kim et al, ATVB 2014 Link |
Intratracheal LPS (mouse) |
Attenuates vascular leak and inflammation, reduces mortality |
Letsiou et al, Am J Physiol 2015 Link; Rizzo et al, Am J Physiol 2015 Link |
Cardiac bypass surgery |
Attenuates vascular leak, improves perfusion, improves oxygenation |
Koning, BJA 2016 Link |
Case-reports (human) |
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Condition/disease |
Effect of imatinib |
Reference |
Pulmonary veno-occlusive disease |
Resolution of pulmonary edema, improvement of oxygenation (<24h) |
Overbeek et al, Eur Respir J 2008 Link |
Bleomycin-induced pneumonitis / lung injury |
Resolution of pulmonary edema |
Carnevale-Schianca et al, J Clin Oncol 2011 Link |
Idiopathic pulmonary vascular leak |
Resolution of pulmonary edema, reduction of pulmonary vascular leak |
Aman et al, Am J Respir Crit Care 2013 Link |
Severe systemic capillary leak syndrome |
Loss of fluid and normalization of hematocrit (0.8 before treatment) |
Unpublished |
Pulmonary GvHD with ground glass opacities and severe hypoxemia |
Within 5 days, improvement of SaO2, weaning from Optiflow (FiO2 90%) |
Unpublished |
Drug-induced pneumonitis |
Resolution of pneumonitis, case series |
Langberg, Acta Oncol 2018 Link |
COVID-19 |
Resolution of disease and pulmonary opacities |
Morales-Ortega, Acta Oncol 2018 Link |