1. Cepharanthin, an alkaloid from Stephania cepharantha, inhibits increased pulmonary vascular permeability in an ovine model of sepsis.
- Author
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Murakami K, Cox RA, Hawkins HK, Schmalstieg FC, McGuire RW, Jodoin JM, Traber LD, and Traber DL
- Subjects
- Animals, Benzylisoquinolines, Calcium metabolism, Disease Models, Animal, Female, Hemodynamics drug effects, Humans, Leukocyte Count, Leukocyte Elastase metabolism, Lung blood supply, Lung pathology, Organ Size drug effects, Platelet Count, Pneumonia drug therapy, Pneumonia physiopathology, Pseudomonas Infections complications, Pseudomonas Infections physiopathology, Pseudomonas aeruginosa pathogenicity, Pulmonary Gas Exchange drug effects, Sepsis etiology, Sheep, Smoke Inhalation Injury complications, Smoke Inhalation Injury drug therapy, Smoke Inhalation Injury physiopathology, Stephania chemistry, Alkaloids pharmacology, Capillary Permeability drug effects, Lung drug effects, Sepsis drug therapy, Sepsis physiopathology
- 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.
- Published
- 2003
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