title: Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury.
abstract: Acute lung injury (ALI) during sepsis is characterized by bilateral alveolar infiltrates, lung edema and respiratory failure. Here, we examined the efficacy the DNA methyl transferase (DNMT) inhibitor 5-Aza 2-deoxycytidine (Aza), the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), as well as the combination therapy of Aza and TSA (Aza+TSA) provides in the protection of ALI. In LPS-induced mouse ALI, post-treatment with a single dose of Aza+TSA showed substantial attenuation of adverse lung histopathological changes and inflammation. Importantly, these protective effects were due to substantial macrophage phenotypic changes observed in LPS-stimulated macrophages treated with Aza+TSA as compared with untreated LPS-induced macrophages or LPS-stimulated macrophages treated with either drug alone. Further, we observed significantly lower levels of pro-inflammatory molecules and higher levels of anti-inflammatory molecules in LPS-induced macrophages treated with Aza+TSA than in LPS-induced macrophages treated with either drug alone. The protection was ascribed to dual effects by an inhibition of MAPK-HuR-TNF and activation of STAT3-Bcl2 pathways. Combinatorial treatment with Aza+TSA reduces inflammation and promotes an anti-inflammatory M2 macrophage phenotype in ALI, and has a therapeutic potential for patients with sepsis.
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Thangavel
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Saheli
authors.initials: S
authors.lastname: Samanta
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Sheeja
authors.initials: S
authors.lastname: Rajasingh
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Bahar
authors.initials: B
authors.lastname: Barani
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.affiliation: Cardiovascular Research Institute, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA rjohnson9@kumc.edu.
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000077209:Decitabine; D004338:Drug Combinations; D019446:Endotoxemia / Q000150:complications / Q000473:pathology; D044127:Epigenesis, Genetic / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D018805:Sepsis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004338:Drug Combinations; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; C012589:trichostatin A; D000077209:Decitabine; D008780:Methyltransferases; D006655:Histone Deacetylases; D001374:Azacitidine
keywords: Acute lung injury; Epigenetic modifiers; Histone deacetylase inhibitor; Inflammation and apoptosis; Sepsis