Bosutinib reduces endothelial permeability and organ failure in a rat polytrauma transfusion model.

Abstract

BACKGROUND:

Trauma-induced shock is associated with endothelial dysfunction. We examined whether the tyrosine kinase inhibitor bosutinib as an adjunct therapy to a balanced blood component resuscitation strategy reduces trauma-induced endothelial permeability, thereby improving shock reversal and limiting transfusion requirements and organ failure in a rat polytrauma transfusion model.

METHODS:

Male Sprague-Dawley rats (n=13 per group) were traumatised and exsanguinated until a MAP of 40 mm Hg was reached, then randomised to two groups: red blood cells, plasma and platelets in a 1:1:1 ratio with either bosutinib or vehicle. Controls were randomised to sham (median laparotomy, no trauma) with bosutinib or vehicle. Organs were harvested for histology and wet/dry (W/D) weight ratio.

RESULTS:

Traumatic injury resulted in shock, with higher lactate levels compared with controls. In trauma-induced shock, the resuscitation volume needed to obtain a MAP of 60 mm Hg was lower in bosutinib-treated animals (2.8 [2.7-3.2] ml kg-1) compared with vehicle (6.1 [5.1-7.2] ml kg-1, P<0.001). Lactate levels in the bosutinib group were 2.9 [1.7-4.8] mM compared with 6.2 [3.1-14.1] mM in the vehicle group (P=0.06). Bosutinib compared with vehicle reduced lung vascular leakage (W/D ratio of 5.1 [4.6-5.3] vs 5.7 [5.4-6.0] (P=0.046) and lung injury scores (P=0.027).

CONCLUSIONS:

Bosutinib as an adjunct therapy to a balanced transfusion strategy reduced resuscitation volume, improved shock reversal, and reduced vascular leak and organ injury in a rat polytrauma model.

• Authors: Derek J B Kleinveld, Liza Botros, M Adrie W Maas, Jesper Kers, Jurjan Aman, Markus W Hollmann, Nicole P Juffermans
• Journal: British journal of anaesthesia (Br J Anaesth) Vol. 126 Issue 5 Pg. 958-966 (May 2021) ISSN: 1471-6771 [Electronic] England
• PMID: 33685634 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Aniline Compounds
• Nitriles
• Protein Kinase Inhibitors
• Quinolines
• Lactic Acid
• bosutinib

Topics

• Aniline Compounds (pharmacology)
• Animals
• Blood Transfusion (methods)
• Disease Models, Animal
• Endothelium, Vascular (metabolism, pathology)
• Lactic Acid (metabolism)
• Lung Injury (drug therapy, etiology)
• Male
• Multiple Trauma (complications, drug therapy, physiopathology)
• Nitriles (pharmacology)
• Permeability (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Quinolines (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Resuscitation (methods)
• Shock (drug therapy, etiology)