Combinatorial therapy with acetylation and methylation modifiers attenuates lung vascular hyperpermeability in endotoxemia-induced mouse inflammatory lung injury.

Abstract

Impairment of tissue fluid homeostasis and migration of inflammatory cells across the vascular endothelial barrier are crucial factors in the pathogenesis of acute lung injury (ALI). The goal for treatment of ALI is to target pathways that lead to profound dysregulation of the lung endothelial barrier. Although studies have shown that chemical epigenetic modifiers can limit lung inflammation in experimental ALI models, studies to date have not examined efficacy of a combination of DNA methyl transferase inhibitor 5-Aza 2-deoxycytidine and histone deacetylase inhibitor trichostatin A (herein referred to as Aza+TSA) after endotoxemia-induced mouse lung injury. We tested the hypothesis that treatment with Aza+TSA after lipopolysaccharide induction of ALI through epigenetic modification of lung endothelial cells prevents inflammatory lung injury. Combinatorial treatment with Aza+TSA mitigated the increased endothelial permeability response after lipopolysaccharide challenge. In addition, we observed reduced lung inflammation and lung injury. Aza+TSA also significantly reduced mortality in the ALI model. The protection was ascribed to inhibition of the eNOS-Cav1-MLC2 signaling pathway and enhanced acetylation of histone markers on the vascular endothelial-cadherin promoter. In summary, these data show for the first time the efficacy of combinatorial Aza+TSA therapy in preventing ALI in lipopolysaccharide-induced endotoxemia and raise the possibility of an essential role of DNA methyl transferase and histone deacetylase in the mechanism of ALI.

• Authors: Jayakumar Thangavel, Asrar B Malik, Harold K Elias, Sheeja Rajasingh, Andrew D Simpson, Premanand K Sundivakkam, Stephen M Vogel, Yu-Ting Xuan, Buddhadeb Dawn, Johnson Rajasingh
• Journal: The American journal of pathology (Am J Pathol) Vol. 184 Issue 8 Pg. 2237-49 (Aug 2014) ISSN: 1525-2191 [Electronic] United States
• PMID: 24929240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Hydroxamic Acids
• trichostatin A
• Decitabine
• Azacitidine

Topics

• Acetylation
• Acute Lung Injury (enzymology, pathology)
• Animals
• Azacitidine (administration & dosage, analogs & derivatives)
• Blotting, Western
• Capillary Permeability (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromatin Immunoprecipitation
• Decitabine
• Disease Models, Animal
• Drug Therapy, Combination
• Endothelial Cells (drug effects)
• Endotoxemia (enzymology, pathology)
• Enzyme Inhibitors (administration & dosage)
• Flow Cytometry
• Fluorescent Antibody Technique
• Hydroxamic Acids (administration & dosage)
• In Situ Nick-End Labeling
• Inflammation (enzymology, pathology)
• Lung (drug effects)
• Male
• Methylation
• Mice
• Mice, Inbred C57BL
• Real-Time Polymerase Chain Reaction