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

Published online

Journal Article

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 30x10Escherichia coli (strain 19138) vs saline (n = 24). Half the infected mice were administered Trichostatin A (TSA) 30 minutes 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 vs. 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 to scrambled siRNA. CONCLUSION: HDAC7 appears to play a key role in the inflammatory response that leads to ALI after gram-negative pneumonia in mice.

Full Text

Duke Authors

Cited Authors

  • Kasotakis, G; Kintsurashvili, E; Galvan, MD; Graham, C; Purves, JT; Agarwal, S; Corcoran, DL; Sullenger, BA; Palmer, SM; Remick, DG

Published Date

  • May 2, 2019

Published In

PubMed ID

  • 31083049

Pubmed Central ID

  • 31083049

Electronic International Standard Serial Number (EISSN)

  • 1540-0514

Digital Object Identifier (DOI)

  • 10.1097/SHK.0000000000001372

Language

  • eng

Conference Location

  • United States