Delayed treatment with platelet activating factor receptor antagonist web 2086 attenuates pulmonary dysfunction in porcine endotoxin shock.
The triazolodiazepine WEB 2086, a specific platelet activating factor (PAF) receptor antagonist, has previously been shown to prevent pulmonary hypertension, hypoxia, and bronchoconstriction when given before bacterial lipopolysaccharide (LPS). The aim of the present study was to examine whether WEB 2086 reduced these changes even when given after the onset of LPS-induced shock. In a randomized trial LPS was given intravenously (i.v.) in a dose of 1 microgram/kg/h for 8 hours to anesthetized, ventilated pigs. Ten animals received LPS and WEB 2086, 10 mg/kg/h i.v. for 6.5 hours, beginning 1.5 hours after LPS. Ten control animals received LPS and saline. During treatment with WEB 2086, pulmonary hypertension was significantly attenuated compared with the findings in the control group. Gas exchange, airway pressure, extravascular lung water levels, intrapulmonary shunt, and cathepsin B levels in plasma showed a trend toward improvement but the group differences were not statistically significant. These data indicate that the PAF antagonist WEB 2086 can partially block pulmonary dysfunction and enzyme release from inflammatory cells when given during ongoing LPS shock in pigs, and that PAF may be an important mediator of the cardiopulmonary changes seen in septic shock.
Department of Surgery, University of Munich, Germany.
M
M
Siebeck
J
J
Kohl
S
S
Endres
M
M
Spannagl
W
W
Machleidt
D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D001794:Blood Pressure; D002401:Cathepsin B / Q000097:blood; D003404:Creatinine / Q000097:blood; D015633:Extravascular Lung Water / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D008070:Lipopolysaccharides; D008168:Lung / Q000503:physiopathology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011651:Pulmonary Artery / Q000503:physiopathology; D011659:Pulmonary Gas Exchange; D012475:Salmonella; D012772:Shock, Septic / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D013552:Swine; D013556:Swine, Miniature; D014230:Triazoles / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014655:Vascular Resistance
D001381:Azepines; D008070:Lipopolysaccharides; D010972:Platelet Activating Factor; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C052518:WEB 2086; D003404:Creatinine; D002401:Cathepsin B