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

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 30×10Escherichia 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.

Duke Scholars

Author J Todd Purves Urology

Author Suresh Kumar Agarwal Jr. Trauma, Acute, and Critical Care Surgery

Author Bruce Alan Sullenger Surgery, Surgical Sciences

Author Scott Michael Palmer Jr. Medicine, Pulmonary, Allergy, and Critical Care Medicine