Tubastatin A prevents hemorrhage-induced endothelial barrier dysfunction

Peter J. Bruhn, Vahagn C. Nikolian, Ihab Halaweish, Zhigang Chang, Martin Sillesen, Baoling Liu, Yongqing Li, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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% CO 2, 95% N 2, 20-48 hours). Expression of acetylated tubulin and hypoxia-inducible factor 1α 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 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.

Original languageEnglish (US)
Pages (from-to)386-392
Number of pages7
JournalJournal of Trauma and Acute Care Surgery
Issue number2
StatePublished - Feb 1 2018
Externally publishedYes


  • Endothelial barrier dysfunction
  • acute lung injury
  • endothelial hyperpermeability
  • histone deacetylase inhibitors
  • injury

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Surgery


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