title: A 21-aminosteroid, U-74006F, attenuates endotoxin-induced lung injury in awake sheep.
abstract: The purpose of the present study was to examine the efficacy of U-74006F, a 21-aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6-keto-prostaglandin (PG) F1 alpha in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 microgram/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U-74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U-74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U-74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6-keto-PGF1 alpha levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U-74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.
authors.affiliation: First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan. keishik@hsp.md.shinshu-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Kubo
authors.forename: T
authors.initials: T
authors.lastname: Amari
authors.forename: T
authors.initials: T
authors.lastname: Kaneki
authors.forename: M
authors.initials: M
authors.lastname: Hanaoka
authors.forename: T
authors.initials: T
authors.lastname: Hayano
authors.forename: T
authors.initials: T
authors.lastname: Miyahara
authors.forename: S
authors.initials: S
authors.lastname: Koyama
authors.forename: T
authors.initials: T
authors.lastname: Koizumi
authors.forename: K
authors.initials: K
authors.lastname: Fujimoto
authors.forename: T
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001784:Blood Gas Analysis; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008196:Lymph / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D011281:Pregnatrienes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011652:Pulmonary Circulation / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology* / Q000503:physiopathology; D012756:Sheep; D013929:Thromboxane B2 / Q000378:metabolism; D014851:Wakefulness
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D011281:Pregnatrienes; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C053355:tirilazad