title: Cepharanthin, an alkaloid from Stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsis.
abstract: Sepsis is a life-threatening event when it occurs in patients suffering from smoke inhalation injury. Pneumonia is one of the most frequent sources of infection in sepsis. Activated leukocytes likely play a role in the pathogenesis of sepsis. Cepharanthin is a biscoclaurine alkaloid that reportedly inhibits the activation of neutrophils. In this study, we investigated the effects of cephranthin on a post-smoke inhalation model of sepsis in sheep. Female sheep (n = 15) were surgically prepared for the study. After 5 days recovery from the operative procedures, tracheostomy was performed in all animals and 48 breaths of cotton smoke (<40 degrees C) were given via a modified bee smoker under halothane anesthesia. After smoke insufflation, Pseudomonas aeruginosa (5 x 109 cfu/kg) was instilled into the airway using a bronchoscope. All of the animals were mechanically ventilated with 100% O(2). Cepharanthin (1.3 mg/kg/h) was infused in five sheep continuously beginning 1 h after the insult and thereafter for the remainder of the 24-h study period. Control animals (n = 6) were treated with 5% dextrose as a vehicle control. Cepharanthin significantly attenuated changes in lung histology as well as in lung wet/dry weight ratio. An in vitro study revealed that cepharanthin inhibited the release of neutrophil elastase from isolated neutrophils stimulated with either formyl-methyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate with an IC(50) of 60 microM. Cepharanthin also inhibited the fMLP-induced increase in intracellular calcium levels of neutrophils. This result indicates cepharanthin inhibits protein kinase C or a more downstream signaling pathway in neutrophil activation. In conclusion, cepharanthin attenuates acute lung injury and septic shock after smoke inhalation in sheep.
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch and Shriners Burn Hospital, 610 Texas Avenue, Galveston, TX 77555, USA.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murakami
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Hal K
authors.initials: HK
authors.lastname: Hawkins
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schmalstieg
authors.forename: Roy W
authors.initials: RW
authors.lastname: McGuire
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jodoin
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D044182:Benzylisoquinolines; D002118:Calcium / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010976:Platelet Count; D011014:Pneumonia / Q000188:drug therapy / Q000503:physiopathology; D011552:Pseudomonas Infections / Q000150:complications / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D031607:Stephania / Q000737:chemistry; D052117:Benzodioxoles
chemical_list: D000470:Alkaloids; D044182:Benzylisoquinolines; D002118:Calcium; D019272:Leukocyte Elastase; C006947:cepharanthine; D052117:Benzodioxoles