Histone Deacetylase 7 Inhibition in a Murine Model of Gram-Negative Pneumonia-Induced Acute Lung Injury

George Kasotakis*, Ekaterina Kintsurashvili, Manuel D. Galvan, Christopher Graham, J. Todd Purves, Suresh Agarwal, David L. Corcoran, Bruce A. Sullenger, Scott M. Palmer, Daniel G. Remick

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background:Pulmonary infections remain the most common cause of Acute Respiratory Distress Syndrome (ARDS), a pulmonary inflammatory disease with high mortality, for which no targeted therapy currently exists. We have previously demonstrated an ameliorated syndrome with early, broad spectrum Histone Deacetylase (HDAC) inhibition in a murine model of gram-negative pneumonia-induced Acute Lung Injury (ALI), the underlying pulmonary pathologic phenotype leading to ARDS. With the current project we aim to determine if selective inhibition of a specific HDAC leads to a similar pro-survival phenotype, potentially pointing to a future therapeutic target.Methods:C57Bl/6 mice underwent endotracheal instillation of 30×106Escherichia coli (strain 19138) versus saline (n = 24). Half the infected mice were administered Trichostatin A (TSA) 30 min later. All animals were sacrificed 6 h later for tissue sampling and HDAC quantification, while another set of animals (n = 24) was followed to determine survival. Experiments were repeated with selective siRNA inhibition of the HDAC demonstrating the greatest inhibition versus scrambled siRNA (n = 24).Results:TSA significantly ameliorated the inflammatory phenotype and improved survival in infected-ALI mice, and HDAC7 was the HDAC with the greatest transcription and protein translation suppression. Similar results were obtained with selective HDAC7 siRNA inhibition compared with scrambled siRNA.Conclusion:HDAC7 appears to play a key role in the inflammatory response that leads to ALI after gram-negative pneumonia in mice.

Original languageEnglish
Pages (from-to)344-351
Number of pages8
JournalShock
Volume53
Issue number3
DOIs
StatePublished - 1 Mar 2020
Externally publishedYes

Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Epigenetic modification
  • Histone deacetylase inhibition
  • SiRNA
  • Trichostatin-A

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