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).