Matthew Quinn1, Matthew McMillin1, Cheryl Galindo1, Gabriel Frampton1, Hae Yong Pae1, Sharon DeMorrow2. 1. Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA. 2. Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX, USA; Digestive Disease Research Center, Scott & White Hospital, USA; Central Texas Veterans Health Care System, Temple, TX, USA. Electronic address: demorrow@medicine.tamhsc.edu.
Abstract
BACKGROUND: The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier. METHODS: Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestatic rats, or bile acid treatment, in the presence of a Rac1 inhibitor. RESULTS: Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability. CONCLUSIONS: These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions.
BACKGROUND: The blood brain barrier tightly regulates the passage of molecules into the brain and becomes leaky following obstructive cholestasis. The aim of this study was to determine if increased serum bile acids observed during cholestasis permeabilize the blood brain barrier. METHODS:Rats underwent bile duct ligation or deoxycholic or chenodeoxycholic acid injections and blood brain barrier permeability assessed. In vitro, the permeability of rat brain microvessel endothelial cell monolayers, the expression and phosphorylation of occludin, ZO-1 and ZO-2 as well as the activity of Rac1 was assessed after treatment with plasma from cholestaticrats, or bile acid treatment, in the presence of a Rac1 inhibitor. RESULTS: Blood brain barrier permeability was increased in vivo and in vitro following bile duct ligation or treatment with bile acids. Associated with the bile acid-stimulated increase in endothelial cell monolayer permeability was elevated Rac1 activity and increased phosphorylation of occludin. Pretreatment of endothelial cell monolayers with a Rac1 inhibitor prevented the effects of bile acid treatment on occludin phosphorylation and monolayer permeability. CONCLUSIONS: These data suggest that increased circulating serum bile acids may contribute to the increased permeability of the blood brain barrier seen during obstructive cholestasis via disruption of tight junctions.
Authors: A J Lechner; A Velasquez; K R Knudsen; C A Johanns; T F Tracy; G M Matuschak Journal: Am J Respir Crit Care Med Date: 1998-05 Impact factor: 21.405
Authors: Matthew McMillin; Gabriel Frampton; Matthew Quinn; Samir Ashfaq; Mario de los Santos; Stephanie Grant; Sharon DeMorrow Journal: Am J Pathol Date: 2015-12-09 Impact factor: 4.307
Authors: Matthew A McMillin; Gabriel A Frampton; Andrew P Seiwell; Nisha S Patel; Amber N Jacobs; Sharon DeMorrow Journal: Lab Invest Date: 2015-06-01 Impact factor: 5.662