George Kasotakis1, Ekaterina Kintsurashvili2, Manuel D Galvan2, Christopher Graham2, J Todd Purves1, Suresh Agarwal1, David L Corcoran3, Bruce A Sullenger1, Scott M Palmer4, Daniel G Remick5. 1. Department of Surgery, Duke University School of Medicine, Durham, North Carolina. 2. Department of Surgery, Boston University School of Medicine, Boston, Massachusetts. 3. Center for Genomic and Computational Biology, Duke University, Durham, North Carolina. 4. Department of Medicine, Duke University School of Medicine, Durham, North Carolina. 5. Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts.
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 30×10Escherichia 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.
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.
Authors: Giacomo Bellani; John G Laffey; Tài Pham; Eddy Fan; Laurent Brochard; Andres Esteban; Luciano Gattinoni; Frank van Haren; Anders Larsson; Daniel F McAuley; Marco Ranieri; Gordon Rubenfeld; B Taylor Thompson; Hermann Wrigge; Arthur S Slutsky; Antonio Pesenti Journal: JAMA Date: 2016-02-23 Impact factor: 56.272
Authors: George Kasotakis; Manuel Galvan; Elizabeth King; Beda Sarkar; Arthur Stucchi; Joseph P Mizgerd; Peter A Burke; Daniel Remick Journal: J Trauma Acute Care Surg Date: 2017-04 Impact factor: 3.313
Authors: W Y Park; R B Goodman; K P Steinberg; J T Ruzinski; F Radella; D R Park; J Pugin; S J Skerrett; L D Hudson; T R Martin Journal: Am J Respir Crit Care Med Date: 2001-11-15 Impact factor: 21.405
Authors: Gordon D Rubenfeld; Ellen Caldwell; Eve Peabody; Jim Weaver; Diane P Martin; Margaret Neff; Eric J Stern; Leonard D Hudson Journal: N Engl J Med Date: 2005-10-20 Impact factor: 91.245
Authors: Wei Chong; Yongqing Li; Baoling Liu; Ting Zhao; Eugene Y Fukudome; Zhengcai Liu; William M Smith; George C Velmahos; Marc A deMoya; Hasan B Alam Journal: J Surg Res Date: 2012-07-26 Impact factor: 2.192
Authors: George Kasotakis; J Todd Purves; Suresh Agarwal; Bruce A Sullenger; Ekaterina Kintsurashvili; Manuel D Galvan; Christopher Graham; David L Corcoran; Scott M Palmer; Daniel G Remick Journal: Shock Date: 2020-03 Impact factor: 3.533
Authors: Patrick C Bradshaw; William A Seeds; Alexandra C Miller; Vikrant R Mahajan; William M Curtis Journal: Oxid Med Cell Longev Date: 2020-09-09 Impact factor: 6.543