Abstract 15634: Epigenetic Modifiers Reduce Inflammation and Modulate Macrophage Phenotype to Attenuate Endotoxemia-Induced Acute Lung Injury
Introduction: Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema, and respiratory failure. Although chemical epigenetic modifiers can potentially limit lung inflammation, to date no study has examined the efficacy of DNA methyl transferase (DNMT) inhibitor Aza (5-Aza 2-deoxycytidine) and histone deacetylase (HDAC) inhibitor TSA (Trichostatin A) combination therapy (Aza+TSA) on inflammation, apoptosis and survival in sepsis.
Hypothesis: Therapy with Aza+TSA will modulate cytokines and macrophages to quench inflammation in ALI.
Methods and Results: In an LPS-induced ALI mouse model, a single dose of Aza+TSA prevented lung inflammation and injury with significant reduction in mortality as compared with mice treated with either Aza or TSA alone. A significant attenuation of adverse lung histopathological changes, and inflammation was noted. RT-PCR array data showed that LPS-induced primary macrophages expressed mRNA transcripts of pro-inflammatory chemokines (ccl2, ccl3, ccl4, ccl5, ccl7, CD40, cxcl10 and cxcl12) and cytokines (IL-1α, IL-1β, IL-1R, IL-6, IL-18, ITGβ2, lymphotoxin-β and TNFα). These proinflammatory molecules were significantly reduced after treatment with Aza+TSA. We also observed significantly higher levels of IL-10 and IL-10R mRNA expression in LPS-induced macrophages treated with Aza+TSA rather than either drug alone. Importantly, our FACS data showed a significant increase in the expression of M2 markers CD23 and CD124 in LPS-induced macrophages treated with Aza+TSA compared with untreated LPS-stimulated cells and control cells (Figure).
Conclusions: Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti-inflammatory M2 macrophage phenotype in the lung during sepsis. This novel epigenetic therapy has therapeutic potential for patients with sepsis and ALI.
Author Disclosures: B. Barani: None. J. Thangavel: None. S. Rajasingh: None. Y. Xuan: None. B. Dawn: None. J. Rajasingh: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.