Abstract 15604: Combinatorial Treatment with HDAC6 and DNA Methylation Modifiers in Attenuating Lung Vascular Hyperpermeability in LPS-induced Inflammatory Lung Injury
Introduction: The pathogenesis of acute lung injury (ALI) is characterized by progressive respiratory failure with bilateral alveolar infiltrates and lung edema due to severe disruption of the lung vascular endothelial barrier. No effective therapy is currently available for prevention and treatment of this condition that is often fatal. No study has examined the efficacy of DNA methyl transferase inhibitor (5-Aza 2-deoxycytidine-Aza) and a specific histone deacetylase6 (HDAC6) inhibitor (Tubastatin A, BioVision, CA) combination (referred to as Aza+HDAC6) on inflammation, apoptosis and endothelial barrier function during sepsis.
Hypothesis: Combinatorial treatment with Aza+HDAC6 would preserve lung microvascular endothelial barrier function and prevent protein-rich tissue fluid accumulation during sepsis.
Methods and Results: The trans-endothelial electrical resistance (TER) and capillary filtration coefficient (Kfc) data show that in LPS-exposed endothelial cells and mice, therapy with Aza+HDAC6 leads to a significant decrease in lung microvascular permeability as compared with either alone. In an ALI mouse model, post-injury treatment with a single dose of Aza+HDAC6 prevented lung injury and afforded a significantly higher survival rate (80%) as compared with mice treated with either Aza or HDAC6 alone. These effects were mediated by a significant attenuation of adverse lung histopathological changes and preservation of endothelial barrier integrity. Aza+HDAC6 also significantly reduced the lung myeloperoxidase content (MPO) and neutrophil infiltration in the ALI model. The protection was ascribed to the activation of Bcl2-STAT3 signaling pathway and enhanced acetylation of histone markers on the CD31 promoter.
Conclusions: These data for the first time show the efficacy of Aza+HDAC6 therapy in preventing ALI in LPS-induced endotoxemia, and suggest an essential role of DNMT and HDAC6 in pathogenesis of ALI. This novel combinatorial regimen may improve and prolong the lives of patients with ALI associated with sepsis.
Author Disclosures: J. Rajasingh: None. J. Thangavel: None. S. Rajasingh: None. B. Barani: None. B. Dawn: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.