title: Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury.
abstract: Studies have suggested that ET-1 (endothelin-1) is associated with lung injury, airway inflammation and increased vascular permeability. In the present study we have tested the hypothesis that treatment with a dual ET-1 receptor antagonist will decrease airway obstruction and improve pulmonary function in sheep with combined S+B (smoke inhalation and burn) injury. Twelve sheep received S+B injury using the following protocol: six sheep were treated with tezosentan, an ETA and ETB receptor antagonist, and six sheep received an equivalent volume of vehicle. Physiological and morphological variables were assessed during the 48 h study period and at the end of the study. There was no statistically significant difference in the PaO2/FiO2 (partial pressure of O2 in arterial blood/fraction of O2 in the inspired gas) ratio of the tezosentan-treated animals compared with controls; however, lung lymph flow was significantly higher (P<0.05) in the treated animals. PVRI (pulmonary vascular resistance index) was significantly reduced (P<0.05) in the tezosentan-treated animals. Assessment of NOx (nitric oxide metabolite) levels in plasma and lymph showed significantly elevated (P<0.05) levels in the tezosentan-treated animals compared with levels in untreated sheep. The degree of bronchial obstruction was similar in both treated and control sheep; however, bronchiolar obstruction was reduced in sheep treated with tezosentan. Histopathologically, no difference in the degree of parenchymal injury was detected. In conclusion, administration of a dual ET-1 receptor antagonist prevented an increase in PVRI after injury and reduced the degree of bronchiolar obstruction in sheep with S+B; however, treated sheep showed higher levels of NOx and increased lung lymph flow. Tezosentan treatment was ineffective in protecting against acute lung injury in this model.
authors.affiliation: Shriners Hospital for Children, Galveston, TX 77550, USA. rocox@utmb.edu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cox
authors.forename: Perenlei
authors.initials: P
authors.lastname: Enkhabaatar
authors.forename: Ann S
authors.initials: AS
authors.lastname: Burke
authors.forename: Jiro
authors.initials: J
authors.lastname: Katahira
authors.forename: Katahiro
authors.initials: K
authors.lastname: Shimoda
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chandra
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Traber
authors.forename: David N
authors.initials: DN
authors.lastname: Herndon
authors.forename: Hal K
authors.initials: HK
authors.lastname: Hawkins
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Traber
mesh_terms: D000818:Animals; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005260:Female; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D012756:Sheep; D015208:Smoke Inhalation Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013777:Tetrazoles / Q000627:therapeutic use*; D014655:Vascular Resistance
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; D009569:Nitric Oxide; C120582:tezosentan; D010100:Oxygen