title: (-)-Deprenyl inhibits thermal injury-induced apoptotic signaling and hyperpermeability in microvascular endothelial cells.
abstract: Burn injury is associated with a significant leak of intravascular fluid into the interstitial space, requiring large amounts of volume resuscitation. Activation of the intrinsic (mitochondrial) apoptotic pathway has been associated with vascular hyperpermeability. We hypothesized that vascular hyperpermeability following burns is also mediated via this pathway. The purpose of this study was to investigate whether (-)-deprenyl, a drug with antioxidant and antiapoptotic properties, could attenuate burn induced-apoptotic signaling and hyperpermeability. Male Sprague-Dawley rats were assigned to sham or experimental groups. The experimental rats underwent a 30 to 40% TBSA full-thickness burn. Serum was collected from all rats at 180 minutes postburn. Rat lung microvascular endothelial cell monolayers were exposed to the sham or burn serum; permeability was determined by fluorescein isothiocyanate-tagged albumin flux. Mitochondrial reactive oxygen species formation was measured with dihydrorhodamine 123. The change in mitochondrial membrane potential was determined with JC-1. Cytosolic cytochrome c was measured by enzyme-linked immunosorbent assay. A group of cells in each series was pretreated with (-)-deprenyl (1 microM). Monolayer permeability increased significantly (P<.05) when treated with burn serum. (-)-Deprenyl significantly attenuated the hyperpermeability induced by burn serum (P<.05). Burn serum increased mitochondrial reactive oxygen species levels and reduced mitochondrial membrane potential; these effects were markedly reduced by (-)-deprenyl. Cytochrome c release was increased by treatment with burn serum (P<.05), and this effect was significantly inhibited by (-)-deprenyl (P<.05). Burn serum induces hyperpemeability and activates intrinsic apoptotic signaling in microvascular endothelial cells. (-)-Deprenyl, an antioxidant and antiapoptotic drug, modulates intrinsic apoptotic signaling and attenuates burn-induced hyperpermeability.
authors.affiliation: Department of Surgery, Texas A&M University System Health Science Center College of Medicine, and Scott and White Memorial Hospital, Temple, Texas 76508, USA.
authors.forename: J Greg
authors.initials: JG
authors.lastname: Whaley
authors.forename: Binu
authors.initials: B
authors.lastname: Tharakan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Smith
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Hunter
authors.forename: Ed W
authors.initials: EW
authors.lastname: Childs
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002056:Burns / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D008996:Monoamine Oxidase Inhibitors; D017382:Reactive Oxygen Species; D012642:Selegiline; D045304:Cytochromes c; D053148:Caspase 3