Tubastatin A Prevents Hemorrhage-Induced Endothelial Barrier Dysfunction

Background Microvascular hyperpermeability resulting from endothelial barrier dysfunction (EBD) is associated with worse clinical outcomes in trauma-induced hemorrhagic shock. We have previously shown that treatment with Tubastatin A (TubA), a histone deacetylase 6 inhibitor, improves outcomes in animal models of shock. In this study, we investigate whether TubA treatment may prevent trauma-related EBD. Methods Wistar-Kyoto rats subjected to 40% hemorrhage were treated with TubA or vehicle control. Acute lung injury (ALI) was assessed histologically from tissues harvested 6 hours post-hemorrhage. In vitro, human umbilical vein endothelial cells (HUVECs) were cultured in EGM BulletKit medium. Medium was exchanged for glucose-free Dulbecco’s Modified Eagle Medium (0.5% fetal bovine serum) with or without TubA, and cells were placed in an anoxic chamber (5% CO2, 95% N2, 20-48 hours). Expression of acetylated tubulin and hypoxia-inducible factor 1α (HIF-1α) were measured by Western blot. Soluble Intercellular Adhesion Molecule-1 concentration within the medium, a marker of endothelial integrity, was determined using enzyme-linked immunosorbent assay. Monolayers were assessed for permeability via transwell assays using fluorescein isothiocyanate-labeled albumin. Results Rats treated with TubA had significantly reduced ALI relative to vehicle control. In vitro, TubA significantly attenuated anoxia-induced hyperpermeability, HIF-1α expression, and glycocalyx shedding. Conclusions Our findings demonstrate that TubA prevents hemorrhage-induced ALI in rats. Additionally, we have shown that TubA prevents anoxia-induced EBD in vitro. Taken together, these results suggest that TubA could attenuate microvascular hyperpermeability related to hemorrhagic shock. Level of Evidence n/a (pre-clincal study) Study Type Pre-clinical Conflicts of Interest and Source of Funding: The authors have no conflicts to declare. This research was funded by a grant from the National Institute of Heath, 2 R01-GM084127 awarded to HBA. Meeting presentation: This study was presented at the 2016 annual Clinical Congress of the American College of Surgeons, October 16-20, 2016, Washington, D.C. Corresponding Author: Hasan Alam, MD, FACS, Norman Thompson Professor of Surgery, Head of General Surgery, University of Michigan Health System, 2920 Taubman Center/5331, University of Michigan Hospital, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-5331, alamh@med.umich.edu © 2017 Lippincott Williams & Wilkins, Inc.

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