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.