Timing of valproic acid in acute lung injury: prevention is the best therapy?

Journal Article (Journal Article)

BACKGROUND: Acute lung injury and respiratory distress syndrome is characterized by uncontrolled inflammation of the lungs after a severe inflammatory stimulus. We have previously demonstrated an ameliorated syndrome and improved survival in mice with early administration of valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, while studies in humans have shown no benefit when anti-inflammatories are administered late. The current study tested the hypothesis that early treatment would improve outcomes in our gram-negative pneumonia-induced acute lung injury. MATERIALS AND METHODS: Mice (C57BL/6) had 50 × 106 Escherichia coli (strain 19,138) instilled endotracheally and VPA (250 mg/kg) administered intraperitoneally 3, 4, 6, and 9 h (n = 12/group) later. Six hours after VPA administration, the animals were sacrificed, and bronchoalveolar lavage (BAL) fluid interleukin-6 (IL-6), tumor necrosis factor, neutrophils and macrophages as well as the E coli colony-forming units were quantified. Plasma IL-6 was also measured. A separate group of mice (n = 12/group) were followed prospectively for 7 days to assess survival. RESULTS: BAL IL-6 and tumor necrosis factor as well as plasma IL-6 were significantly lower in the animals administered VPA within 3 h (P < 0.05) but not when administered later (4, 6, 9 h). There was no difference in the BAL E coli colony-forming units, macrophage, or neutrophil numbers at any time point. Survival improved only when VPA was administered within 3 h. CONCLUSIONS: A narrow therapeutic window exists in this murine model of gram-negative pneumonia-induced acute lung injury and likely explains the lack of response in studies with late administration of anti-inflammatory therapies in clinical studies.

Full Text

Duke Authors

Cited Authors

  • Kasotakis, G; Galvan, MD; Osathanugrah, P; Dharia, N; Bufe, L; Breed, Z; Mizgerd, JP; Remick, DG

Published Date

  • December 2017

Published In

Volume / Issue

  • 220 /

Start / End Page

  • 206 - 212

PubMed ID

  • 29180183

Pubmed Central ID

  • PMC5726455

Electronic International Standard Serial Number (EISSN)

  • 1095-8673

Digital Object Identifier (DOI)

  • 10.1016/j.jss.2017.06.088


  • eng

Conference Location

  • United States