Dasatinib increases endothelial permeability leading to pleural effusion

Abstract

Pleural effusion is a frequent side-effect of dasatinib, a second-generation tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. However, the underlying mechanisms remain unknown. We hypothesised that dasatinib alters endothelial integrity, resulting in increased pulmonary vascular endothelial permeability and pleural effusion.To test this, we established the first animal model of dasatinib-related pleural effusion, by treating rats with a daily regimen of high doses of dasatinib (10 mg·kg·day for 8 weeks).Pleural ultrasonography revealed that rats chronically treated with dasatinib developed pleural effusion after 5 weeks. Consistent with these observations, dasatinib led to a rapid and reversible increase in paracellular permeability of human pulmonary endothelial cell monolayers as reflected by increased macromolecule passage, loss of vascular endothelial cadherin and zonula occludens-1 from cell-cell junctions, and the development of actin stress fibres. These results were replicated using human umbilical vein endothelial cells and confirmed by decreased endothelial resistance. Interestingly, we demonstrated that this increased endothelial permeability is a reactive oxygen species (ROS)-dependent mechanism and using a cotreatment with an antioxidant agent,-acetylcysteine.This study shows that dasatinib alters pulmonary endothelial permeability in a ROS-dependent manner and leading to pleural effusion.

Editorial: Molecular Mechanisms in Pulmonary Hypertension and Right Ventricle Dysfunction

“…This study also demonstrates that some of the effects of dasatinib are modulated by Rho-kinase activation, a signaling that is abnormally activated in both Group 1 and Group 3 settings (Guilluy et al, 2009; Collum et al, 2017b). Although parts of these findings are in line with previous studies demonstrating that dasatinib-induced endothelial cell dysfunction is reversible following withdrawal (Phan et al, 2018), it appears clear that this phenomenon cannot be sufficiently explained by ROCK activation or Lyn inhibition alone (Phan et al, 2018). Further work is therefore needed to identify the mechanisms underlying dasatinib induced lung vascular toxicity and PH predisposition (Guignabert et al, 2016).…”

Macrophage Migration Inhibitory Factor (MIF) Inhibition in a Murine Model of Bleomycin-Induced Pulmonary Fibrosis

“…Immunohistochemistry and immunocytofluorescence staining for MIF, CD74, α-smooth muscle (SM) actin, or F4/80 were performed in human and mouse lung paraffin sections [34,35,36,37,38]. Briefly, lung sections (5 μm thickness) were deparaffined and stained with hematoxylin and eosin (Sigma-Aldrich, Saint-Quentin Fallavier, France), Sirius red, Masson’s trichrome, or incubated with retrieval buffer.…”

“…Lung tissues were homogenized and sonicated in RIPA buffer containing protease and phosphatase inhibitors, and 30 µg of protein was used for the detection of CXCR4, CD74, and GAPDH [36,37,38,40,41]. Concentrations of CCL2 in mice serum were evaluated using a specific ELISA kit (R&D Systems, Lille, France) according to the manufacturer’s instructions.…”

Vascular Endothelial Senescence: Pathobiological Insights, Emerging Long Noncoding RNA Targets, Challenges and Therapeutic Opportunities

“…Additional clinical studies were completed using quercetin such as on cerebral blood flow, blood sugar and blood vessel function in type 2 diabetes, hypertension and endothelial dysfunction (see footnote text 1; identifiers NCT01376011, NCT01839344, and NCT01691404), others are ongoing about coronary artery disease progression, glucose absorption in obesity and obesity with type 2 diabetes, and Fanconi Anemia (see footnote text 1; identifiers NCT03943459, NCT00065676, and NCT01720147). Because high doses of dasatinib alone is known to induce pleural effusions in patients, an effect potentially mediated by endothelial permeability ( Phan et al, 2018 ), lower doses of dasatinib will continue to be warranted for clinical applications.…”