Amelioration of endotoxin-induced acute lung injury in pigs by HWA 138 and A 80 2715: new analogs of pentoxifylline.
We have evaluated the potential therapeutic effects of the xanthine derivatives HWA 138 (1-(5 hydroxy-5-methylhexyl)-3-methylxanthine) and A 80,2715 (1-(5 hydroxy-5-methylhexyl)-3-methyl-7-propylxanthine) on acute lung injury in endotoxemic pigs when administered following the septic insult. Salmonella abortus equi endotoxin (LPS) was given as a continuous intravenous infusion of 2 micrograms/kg/h over a period of 8 h. 1 h after the start of the LPS infusion the animals received a bolus injection followed by continuous infusion of A 80,2715 (3 mg/kg + 1.5 mg/kg/h; n = 6), HWA 138 (3 mg/kg + 1.5 mg/kg/h; n = 6), or saline (LPS control; n = 6). Treatment with A 80,2715 or HWA 138 inhibited the LPS-induced increases in the pulmonary artery pressure (p < .05; ANOVA) and in lung wet/dry weight ratio (p < .05), and ameliorated the LPS-induced deterioration in lung mechanics (decreased lung dynamic compliance (p < .05); increased peak airway pressure (p < .05)). Xanthine treatment, however, failed to significantly improve arterial PO2 and did not affect peripheral leukopenia. The results of this study suggest a potential therapeutic role for HWA 138 and A 80,2715 in attenuating endotoxin-induced acute lung injury.
Hoffmann
H
H
Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians Universität München, Germany.
Weis
M
M
Frank
G
G
Birg
A
A
Schönharting
M M
MM
Jochum
M
M
D000818:Animals; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D006439:Hemodynamics; D007262:Infusions, Intravenous; D007958:Leukocyte Count; D007970:Leukopenia / Q000150:complications / Q000473:pathology; D008070:Lipopolysaccharides; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011652:Pulmonary Circulation / Q000187:drug effects; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D012772:Shock, Septic / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D013552:Swine; D013556:Swine, Miniature; D014970:Xanthines / Q000627:therapeutic use*
D001993:Bronchodilator Agents; D008070:Lipopolysaccharides; D014970:Xanthines; C062028:1-(5-hydroxy-5-methylhexyl)-3-methylxanthine; C078398:A 802715; D010431:Pentoxifylline