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Endothelial damage and dysfunction in acute graft-versus-host disease

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Item Type:Article
Title:Endothelial damage and dysfunction in acute graft-versus-host disease
Creators Name:Cordes, S. and Mokhtari, Z. and Bartosova, M. and Mertlitz, S. and Riesner, K. and Shi, Y. and Mengwasser, J. and Kalupa, M. and McGeary, A. and Schleifenbaum, J. and Schrezenmeier, J. and Bullinger, L. and Diaz-Ricart, M. and Palomo, M. and Carrreras, E. and Beutel, G. and Schmitt, C.P. and Beilhack, A. and Penack, O.
Abstract:Clinical studies suggested that endothelial dysfunction and damage could be involved in the development and severity of acute graft-versus-host disease (aGVHD). Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGVHD. In murine experimental aGVHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGVHD target organs. During intestinal aGVHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. Because recent data demonstrated an association of endothelium-related factors and steroid refractory aGVHD (SR-aGVHD), we analyzed human biopsies and murine tissues from SR-aGVHD. We found extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent SR-aGVHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGVHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGVHD. Therapeutic intervention by endothelium-protecting agents is an attractive approach for SR-aGVHD complementing current anti-inflammatory treatment options.
Keywords:Endothelial Cells, Endothelium, Graft vs Host Disease, Steroids, T-Lymphocytes, Animals, Mice
Publisher:Ferra Storti Foundation
Page Range:2147-2160
Date:1 August 2020
Official Publication:https://doi.org/10.3324/haematol.2020.253716
PubMed:View item in PubMed

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