Dasatinib increases endothelial permeability leading to pleural effusion

Area of Science:

• Pulmonary Medicine
• Pharmacology
• Cell Biology

Background:

• Pleural effusion is a common side effect of dasatinib, a tyrosine kinase inhibitor for chronic myelogenous leukaemia.
• The exact mechanisms driving dasatinib-induced pleural effusion are not well understood.

Purpose of the Study:

• To investigate the mechanisms underlying dasatinib-induced pleural effusion.
• To establish an animal model for studying dasatinib-related pleural effusion.

Main Methods:

• Developed a rat model by administering high-dose dasatinib (10 mg·kg-1·day-1 for 8 weeks).
• Assessed pleural effusion using ultrasonography.
• Evaluated pulmonary endothelial cell permeability in vitro using human pulmonary and umbilical vein endothelial cells, measuring macromolecule passage, cell junction protein expression (VE-cadherin, ZO-1), and endothelial resistance.
• Investigated the role of reactive oxygen species (ROS) using an antioxidant (N-acetylcysteine).

Main Results:

• Rats treated with dasatinib developed pleural effusion after 5 weeks.
• Dasatinib increased endothelial permeability in vitro, evidenced by increased macromolecule passage, disrupted cell junctions, and reduced endothelial resistance.
• This increased permeability was found to be ROS-dependent both in vitro and in vivo, as N-acetylcysteine treatment mitigated the effect.

Conclusions:

• Dasatinib alters pulmonary endothelial permeability through a ROS-dependent mechanism.
• This dasatinib-induced endothelial dysfunction contributes to the development of pleural effusion.