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Science

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).

Evidence base

Case reports (human)

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%)

Drug-induced pneumonitis

Resolution of pneumonitis, case series

COVID-19

Resolution of disease and pulmonary opacities

In vivo studies

Model

Effect of imatinib

Reference

Bleomycin-induced lung injury

Anti-inflammatory; anti-fibrotic

Isolated perfused lung model (mouse)

Inhibits lung vascular leak

Miles assay (mouse)

Attenuates vascular leak in skin

Cecal Ligation & Puncture (Sepsis) (mouse)

Attenuates vascular leak in lungs, kidneys

Intratracheal LPS (mouse)

Attenuates pulmonary edema

Ischemia-reperfusion in reperfusion lung

Reduces endothelial cytotoxicity

Miles assay (mouse)

Attenuates vascular leak in skin

Intratracheal LPS (mouse)

Attenuates vascular leak and inflammation, reduces mortality

Cardiac bypass surgery

Attenuates vascular leak, improves perfusion, improves oxygenation

In vitro studies

Model

Effect of imatinib

Reference

Rat aortic endothelial cells

Protects endothelial barrier

Human umbilical vein endothelial cells

Protects endothelial barrier, improves cell-matrix adhesion

Human lung microvascular endothelial cells

Protects endothelial barrier

Immortalized endothelial cells

Protects endothelial barrier

Human umbilical vein endothelial cells

Protects endothelial barrier

Mouse lung microvascular endothelial cells

Protects endothelial barrier

Human umbilical vein endothelial cells

Protects endothelial barrier