The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs

• Published in: American journal of respiratory and critical care medicine 1997-03, Vol.155 (3), p.928-936
• Main Authors: HASEGAWA, N, OKA, Y, NAKAYAMA, M, BERRY, G. J, BURSTEN, S, RICE, G, RAFFIN, T. A
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - administration & dosage; Adjuvants, Immunologic - therapeutic use; Animals; Biological and medical sciences; Disease Models, Animal; Female; Hemodynamics; Lung - pathology; Male; Medical sciences; Miscellaneous; Pentoxifylline - administration & dosage; Pentoxifylline - analogs & derivatives; Pentoxifylline - therapeutic use; Pharmacology. Drug treatments; Phosphatidic Acids - antagonists & inhibitors; Pseudomonas Infections; Respiratory Distress Syndrome, Adult - etiology; Respiratory Distress Syndrome, Adult - prevention & control; Shock, Septic - microbiology; Shock, Septic - physiopathology; Shock, Septic - prevention & control; Swine; Swine, Miniature; Time Factors
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/ajrccm.155.3.9117028

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.