title: Valproic acid mitigates the inflammatory response and prevents acute respiratory distress syndrome in a murine model of Escherichia coli pneumonia at the expense of bacterial clearance.
abstract: Histone deacetylase inhibitors (HDACI) are members of a family of epigenetic modifying agents with broad anti-inflammatory properties. These anti-inflammatory properties may have important therapeutic implications in acute respiratory distress syndrome (ARDS). However, administration of HDACI may create an immunosuppressive environment conducive to bacterial growth. Accordingly, the aim of the current study is to investigate the effect of HDACI valproic acid (VPA) on host inflammatory response and bacterial burden in a murine model of Escherichia coli pneumonia-induced ARDS.
  
  
  
  ARDS was induced in male C57BL6 mice (n = 24) by endotracheal instillation of 3 × 10 E. coli. VPA (250 mg/kg) was administered 30 minutes after E. coli instillation in the intervention group. Blood samples were collected at 3 and 6 hours, and animals were sacrificed at 6 hours. Bronchoalveolar lavage (BAL) was performed, and tissue specimens were harvested. Cytokine levels were measured in blood and BAL, and so was transalveolar protein transit. Cell counts and colony forming units were quantified in BAL fluid.
  
  
  
  VPA reduced neutrophil influx into the lungs and local tissue destruction through decreased myeloperoxidase activity. It also ameliorated the pulmonary and systemic inflammatory response. This led to greater bacterial proliferation in the pulmonary parenchyma.
  
  
  
  Administration of VPA in a clinically relevant bacterial model of murine ARDS mitigates the host inflammatory response, essentially preventing ARDS, but creates an immunosuppressive environment that favors bacterial overgrowth.
authors.affiliation: From the Department of Surgery (G.K., M.G., E.K., B.S., A.S., P.A.B.), Departments of Medicine, Microbiology and Biochemistry, Pulmonary Center (J.P.M.), and Department of Pathology and Laboratory Medicine (D.R.), Boston University School of Medicine, Boston, Massachusetts.
authors.forename: George
authors.initials: G
authors.lastname: Kasotakis
authors.forename: Manuel
authors.initials: M
authors.lastname: Galvan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: King
authors.forename: Beda
authors.initials: B
authors.lastname: Sarkar
authors.forename: Arthur
authors.initials: A
authors.lastname: Stucchi
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.forename: Peter A
authors.initials: PA
authors.lastname: Burke
authors.forename: Daniel
authors.initials: D
authors.lastname: Remick
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000254:growth & development; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology*; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000517:prevention & control*; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D014635:Valproic Acid; D009195:Peroxidase