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Tubastatin A prevents hemorrhage-induced endothelial barrier dysfunction.

ABSTRACT: 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 posthemorrhage. 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 1? was 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, hypoxia-inducible factor 1? 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.

SUBMITTER: Bruhn PJ

PROVIDER: S-EPMC5780204 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Tubastatin A prevents hemorrhage-induced endothelial barrier dysfunction.

Bruhn Peter J PJ Nikolian Vahagn C VC Halaweish Ihab I Chang Zhigang Z Sillesen Martin M Liu Baoling B Li Yongqing Y Alam Hasan B HB

The journal of trauma and acute care surgery 20180201 2

<h4>Background</h4>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.<h4>Methods</h4>Wistar-Kyoto rats subjected to 40% hemorrhage were treated with TubA o ...[more]

PMID: 29194316

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Tubastatin A prevents hemorrhage-induced endothelial barrier dysfunction.

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Tubastatin A prevents hemorrhage-induced endothelial barrier dysfunction.

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