THE EFFECTS OF POSTTREATMENT WITH LISOFYLLINE, A PHOSPHATIDIC-ACID GENERATION INHIBITOR, ON SEPSIS-INDUCED ACUTE LUNG INJURY IN PIGS

The effects of lisofylline [(R)-1-(5-hydroxyhexyl)-3,7-dimethylxanthin e] (LSF), an inhibitor of de novo phosphatidic acid (PA) generation, o n sepsis-induced acute lung injury was studied using Hanford minipigs weighing 18 to 25 kg. Sepsis was induced by an intravenous infusion of Pseudomonas aeruginosa (1 x 10(6)/colony-forming units/kg/min over 2 h). Saline was used as the control vehicle. Six groups were studied: s aline control group (SALINE: n = 5); sepsis control group (SEPSIS: n = 5); LSF control group (LSF: n = 5), which received a 25-mg/kg bolus o f LSF 30 min before time zero followed by continuous infusion of 10 mg /kg/h throughout the study; LSF-treated septic groups, which were trea ted with LSF 30 min prior to sepsis (Pre: n = 5), 1 h postonset (Post- 1 h: n = 8) or 2 h postonset (Post-2 h: n = 8) of the bacterial infusi on. Hemodynamics, Pa-O2, neutrophil counts, and plasma porcine tumor n ecrosis factor-alpha concentrations were monitored for 6 h. After the minipigs were killed, lung tissue was sampled to measure wet-to-dry we ight ratio (W/D), tissue albumin index (TAI), thiobarbituric acid-reac tive material content (TBARM), and myeloperoxidase (MPO) activity. Com pared with the SALINE group, the SEPSIS group showed significant syste mic hypotension, pulmonary hypertension, arterial hypoxemia, neutropen ia, and increase in TNF-alpha, MPO activity, W/D, TBARM, and TAI. LSF treatment attenuated sepsis-induced pulmonary hypertension, neutropeni a, and hypoxemia, and increased MPO activity and lung injury measureme nts in the Pre and Post-1 h groups, but its efficacy was blunted in th e Post-2. h group. Plasma TNF-alpha was decreased only in the Pre grou p. Thus, inhibition of intracellular PA generation through de novo pat hways attenuates sepsis-induced acute lung injury.