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Got it!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).
Condition/disease
Effect of imatinib
Reference
Pulmonary veno-occlusive disease
Resolution of pulmonary edema, improvement of oxygenation (<24h)
Bleomycin-induced pneumonitis / lung injury
Resolution of pulmonary edema
Idiopathic pulmonary vascular leak
Resolution of pulmonary edema, reduction of pulmonary vascular leak
Severe systemic capillary leak syndrome
Loss of fluid and normalization of hematocrit (0.8 before treatment)
Pulmonary GvHD with ground glass opacities and severe hypoxemia
Within 5 days, improvement of SaO2, weaning from Optiflow (FiO2 90%)
Model
Effect of imatinib
Reference
Cecal Ligation & Puncture (Sepsis) (mouse)
Attenuates vascular leak in lungs, kidneys
Ischemia-reperfusion in reperfusion lung
Reduces endothelial cytotoxicity
Intratracheal LPS (mouse)
Attenuates vascular leak and inflammation, reduces mortality
Cardiac bypass surgery
Attenuates vascular leak, improves perfusion, improves oxygenation
Model
Effect of imatinib
Reference
Rat aortic endothelial cells
Protects endothelial barrier
Human umbilical vein endothelial cells
Protects endothelial barrier, improves cell-matrix adhesion
Mouse lung microvascular endothelial cells
Protects endothelial barrier
Human umbilical vein endothelial cells
Protects endothelial barrier