Dataset Information

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

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.

SUBMITTER: Kasotakis G

PROVIDER: S-EPMC6824972 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Kasotakis George G Kintsurashvili Ekaterina E Galvan Manuel D MD Graham Christopher C Purves J Todd JT Agarwal Suresh S Corcoran David L DL Sullenger Bruce A BA Palmer Scott M SM Remick Daniel G DG

Shock (Augusta, Ga.) 20200301 3

<h4>Background</h4>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 pro ...[more]

PMID: 31083049

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Project description:With advances in supportive therapy in the last two decades, mortality rates from ALI/ARDS have improved somewhat, but remain around 30 to 40% with significant morbidity in survivors. Several promising treatments are in various stages of evaluation, but many have failed to prove beneficial in large randomized clinical trials (RCT). The first definitive step forward in ALI therapeutics occurred recently as a result of a large RCT demonstrating a mortality decrease from 40 to 31% with the use of low-volume ventilation strategies. From this, it is clear that the opportunity for successful intervention in ALI exists. However, therapeutic advances remain frustrated by the lack of complete understanding of ALI pathophysiology. This stresses the importance of integrating basic and clinical research of the molecular pathogenesis of this disease. The conclusions of a recent National Heart, Lung, and Blood Institute (NHLBI) Working Group on ALI support this type of research as a priority for future investigations of ALI. One of the areas of research given priority by this ALI Working Group is the issue of ALI severity progression and the role of cells of innate immunity in this process. Currently, the processes that determine which ALI patients progress to ARDS and which do not are unclear. As with many phenotype differences, there is most likely a genetic component involved. The basis for this has been demonstrated. For example, a surfactant protein B (SP-B) polymorphism appears to increase a patient’s risk of developing ALI from pneumonia. Additionally, a polymorphism in the promoter region of the gene for interleukin-6 (IL-6) has been associated with a poor prognosis in patients with ARDS. Understanding the intracellular processes of these genes and the cells expressing them in ALI progression could lead to the identification of molecular markers of ALI severity and eventually to the development of targeted therapies. An examination of genetically uniform animals will provide a clearer insight into the interaction between immune cells in ALI progression as well as guide future human experiments. Keywords: Time Series Design, ALI - acute lung injury, ARDS - acute respiratory distress syndrome, CLP - cecal ligation and puncture

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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