title: 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.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Thangavel
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Harold K
authors.initials: HK
authors.lastname: Elias
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Sheeja
authors.initials: S
authors.lastname: Rajasingh
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Simpson
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Premanand K
authors.initials: PK
authors.lastname: Sundivakkam
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Vogel
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Xuan
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Buddhadeb
authors.initials: B
authors.lastname: Dawn
authors.affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas; Department of Biochemistry and Molecular Biology, Cardiovascular Research Institute, University of Kansas Medical Center, Kansas City, Kansas. Electronic address: rjohnson9@kumc.edu.
authors.forename: Johnson
authors.initials: J
authors.lastname: Rajasingh
mesh_terms: D000107:Acetylation; D055371:Acute Lung Injury / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D000077209:Decitabine; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects; D019446:Endotoxemia / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000187:drug effects*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine