The effects of post-treatment 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-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.
Hasegawa
N
N
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, CA 94305-5236, USA.
Oka
Y
Y
Nakayama
M
M
Berry
G J
GJ
Bursten
S
S
Rice
G
G
Raffin
T A
TA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics; D008168:Lung / Q000473:pathology; D008297:Male; D010431:Pentoxifylline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010712:Phosphatidic Acids / Q000037:antagonists & inhibitors*; D011552:Pseudomonas Infections; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000517:prevention & control*; D012772:Shock, Septic / Q000382:microbiology / Q000503:physiopathology / Q000517:prevention & control*; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors
D000276:Adjuvants, Immunologic; D010712:Phosphatidic Acids; C025189:lisofylline; D010431:Pentoxifylline