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

Autor:	Kasotakis G; Department of Surgery, Duke University School of Medicine, Durham, North Carolina., Kintsurashvili E; Department of Surgery, Boston University School of Medicine, Boston, Massachusetts., Galvan MD; Department of Surgery, Boston University School of Medicine, Boston, Massachusetts., Graham C; Department of Surgery, Boston University School of Medicine, Boston, Massachusetts., Purves JT; Department of Surgery, Duke University School of Medicine, Durham, North Carolina., Agarwal S; Department of Surgery, Duke University School of Medicine, Durham, North Carolina., Corcoran DL; Center for Genomic and Computational Biology, Duke University, Durham, North Carolina., Sullenger BA; Department of Surgery, Duke University School of Medicine, Durham, North Carolina., Palmer SM; Department of Medicine, Duke University School of Medicine, Durham, North Carolina., Remick DG; Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Shock (Augusta, Ga.) [Shock] 2020 Mar; Vol. 53 (3), pp. 344-351.
DOI:	10.1097/SHK.0000000000001372
Abstrakt:	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.
Databáze:	MEDLINE
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