TNF-α and IL-1β Increase Pericyte/Endothelial Cell Co-Culture Permeability

Kerkar, Sid P.; Williams, Marshall V.; Blocksom, Jason M.; Wilson, Robert F.; Tyburski, James G.; Steffes, Christopher P.

doi:10.1016/j.jss.2005.06.033

Cited by 40 publications

(24 citation statements)

References 18 publications

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“…Microvasculature lung pericyte/endothelial cell cocultures exposed to TNF-A, IL-1B and high mobility group box 1 resulted in increased permeability [50,51]. Furthermore, our lab has demonstrated a concentration and time dependant effect of LPS on albumin clearance in microvasculature lung pericyte/endothelial cell co-cultures (Fig.…”

Section: Regulation Of Permeabilitymentioning

confidence: 73%

Pericytes and Their Role in Microvasculature Homeostasis

Edelman

Yang

Tyburski

et al. 2006

Journal of Surgical Research

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Section: Regulation Of Permeabilitymentioning

confidence: 73%

Pericytes and Their Role in Microvasculature Homeostasis

Edelman

Yang

Tyburski

et al. 2006

Journal of Surgical Research

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“…Moreover, findings from ex vivo and in vivo models, being highly sensitive to potential confounders, should be interpreted with caution when assessing the effects of proinflammatory cytokines on the BBB. For example, TNF-α can act on all cells within the neurovascular unit (astrocytes, pericytes, neurons and microvascular endothelial cells) to elicit cellular remodeling, nitric oxide- and glutamate-mediated neurotoxicity, and endothelin-1 upregulation, all of which can contribute directly/indirectly to cerebrovascular endothelial barrier dysfunction [33]–[36], whilst several studies also report evidence of a neuroprotective role for TNF-α in the brain for review see [37].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Blood-Brain Barrier Phenotype by Proinflammatory Cytokines Involves NADPH Oxidase-Dependent ROS Generation: Consequences for Interendothelial Adherens and Tight Junctions

et al. 2014

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Background and ObjectivesBlood-brain barrier (BBB) dysfunction is an integral feature of neurological disorders and involves the action of multiple proinflammatory cytokines on the microvascular endothelial cells lining cerebral capillaries. There is still however, considerable ambiguity throughout the scientific literature regarding the mechanistic role(s) of cytokines in this context, thereby warranting a comprehensive in vitro investigation into how different cytokines may cause dysregulation of adherens and tight junctions leading to BBB permeabilization.MethodsThe present study employs human brain microvascular endothelial cells (HBMvECs) to compare/contrast the effects of TNF-α and IL-6 on BBB characteristics ranging from the expression of interendothelial junction proteins (VE-cadherin, occludin and claudin-5) to endothelial monolayer permeability. The contribution of cytokine-induced NADPH oxidase activation to altered barrier phenotype was also investigated.ResultsIn response to treatment with either TNF-α or IL-6 (0–100 ng/ml, 0–24 hrs), our studies consistently demonstrated significant dose- and time-dependent decreases in the expression of all interendothelial junction proteins examined, in parallel with dose- and time-dependent increases in ROS generation and HBMvEC permeability. Increased expression and co-association of gp91 and p47, pivotal NADPH oxidase subunits, was also observed in response to either cytokine. Finally, cytokine-dependent effects on junctional protein expression, ROS generation and endothelial permeability could all be attenuated to a comparable extent using a range of antioxidant strategies, which included ROS depleting agents (superoxide dismutase, catalase, N-acetylcysteine, apocynin) and targeted NADPH oxidase blockade (gp91 and p47 siRNA, NSC23766).ConclusionA timely and wide-ranging investigation comparing the permeabilizing actions of TNF-α and IL-6 in HBMvECs is presented, in which we demonstrate how either cytokine can similarly downregulate the expression of interendothelial adherens and tight junction proteins leading to elevation of paracellular permeability. The cytokine-dependent activation of NADPH oxidase leading to ROS generation was also confirmed to be responsible in-part for these events.

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“…11 Relatively simpler and traditional in vitro platforms measure the flux of molecules of various sizes using transwell insert based permeability assays. [12][13][14][15][16] Such works are mostly performed under static conditions without consideration to the fluid shear stress (FSS) conditions that the endothelium is exposed to in vivo. Microfluidic technologies bring in a suite of new possibilities for blood vessel platforms.…”

Section: Introductionmentioning

confidence: 99%

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

et al. 2017

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The inflammatory response in endothelial cells (ECs) leads to an increase in vascular permeability through the formation of gaps. However, the dynamic nature of vascular permeability and external factors involved is still elusive. In this work, we use a biomimetic blood vessel (BBV) microfluidic model to measure in real-time the change in permeability of the EC layer under culture in physiologically relevant flow conditions. This platform studies the dynamics and characterizes vascular permeability when the EC layer is triggered with an inflammatory agent using tracer molecules of three different sizes, and the results are compared to a transwell insert study. We also apply an analytical model to compare the permeability data from the different tracer molecules to understand the physiological and bio-transport significance of endothelial permeability based on the molecule of interest. A computational model of the BBV model is also built to understand the factors influencing transport of molecules of different sizes under flow. The endothelial monolayer cultured under flow in the BBV model was treated with thrombin, a serine protease that induces a rapid and reversible increase in endothelium permeability. On analysis of permeability data, it is found that the transport characteristics for fluorescein isothiocyanate (FITC) dye and FITC Dextran 4k Da molecules are similar in both BBV and transwell models, but FITC Dextran 70k Da molecules show increased permeability in the BBV model as convection flow (Peclet number > 1) influences the molecule transport in the BBV model. We also calculated from permeability data the relative increase in intercellular gap area during thrombin treatment for ECs in the BBV and transwell insert models to be between 12% and 15%. This relative increase was found to be within range of what we quantified from F-actin stained EC layer images. The work highlights the importance of incorporating flow in in vitro vascular models, especially in studies involving transport of large size objects such as antibodies, proteins, nano/micro particles, and cells. Published by AIP Publishing.

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TNF-α and IL-1β Increase Pericyte/Endothelial Cell Co-Culture Permeability

Cited by 40 publications

References 18 publications

Pericytes and Their Role in Microvasculature Homeostasis

Pericytes and Their Role in Microvasculature Homeostasis

Downregulation of Blood-Brain Barrier Phenotype by Proinflammatory Cytokines Involves NADPH Oxidase-Dependent ROS Generation: Consequences for Interendothelial Adherens and Tight Junctions

Characterization of vascular permeability using a biomimetic microfluidic blood vessel model

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