Am. J. Respir. Crit. Care Med., Vol 155, No. 3, 03 1997, 928-936.
The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs
N Hasegawa, Y Oka, M Nakayama, GJ Berry, S Bursten, G Rice and TA Raffin
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, CA 94305-5236, USA.
The effects of lisofylline [(R)-1-(5-hydroxyhexyl)-3,7- dimethylxanthine]
(LSF), an inhibitor of de novo phosphatidic acid (PA) generation, on
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: saline
control group (SALINE: n = 5); sepsis control group (SEPSIS: n = 5); LSF
control group (LSF: n = 5), which received a 25-mg/kgbolus of LSF 30 min
before time zero followed by continuous infusion of 10 mg/kg/h throughout
the study; LSF-treated septic groups, which were treated with LSF 30 min
prior to sepsis (Pre: n = 5), 1 h postonset (Post-1 h: n = 8) or h
postonset (Post-2 h: n = 8) of the bacterial infusion. Hemodynamics PaO2,
neutrophil counts, and plasma porcine tumor necrosis factor-alpha
concentrations were monitored for 6 h. After the minipigs were killed, lung
tissue was sampled to measured wet-to-dry weight ratio (W/D), tissue
albumin index (TAI), thiobarbituric acid-reactive material content (TBARM),
and myeloperoxidase (MPO) activity. Compared with the SALINE group, the
SEPSIS group showed significant systemic hypotension, pulmonary
hypertension, arterial hypoxemia, neutropenia, and increase in TNF- alpha,
MPO activity, W/D, TBARM, and TAI. LSF treatment attenuated sepsis-induced
pulmonary hypertension, neutropenia, and hypoxemia, and increased MPO
activity and lung injury measurements in the Pre and Post- 1 h groups, but
its efficacy was blunted in the Post-2 h group. Plasma TNF-alpha was
decreased only in the Pre group. Thus, inhibition of intracellular PA
generation through de novo pathways attenuates sepsis- induced acute lung
injury.
