Lisofylline prevents leak, but not neutrophil accumulation, in lungs of rats given IL-1 intratracheally

Brooks M. Hybertson 1 , Stuart L. Bursten 2 , Jonathan A. Leff 1 , Young M. Lee 1 , Eric K. Jepson 1 , Chris R. Dewitt 1 , John Zagorski 3 , Hyun G. Cho 4 , and John E. Repine 1 1 The Webb-Waring Institute for Biomedical Research and the Department of Medicine at the University of Colorado Health Sciences Center, Denver, Colorado, 80262; 2 Cell Therapeutics, Inc., Seattle, Washington 98119; 3 National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892; and 4 Yeungnam University, Kyungsan 712-749, Korea Received 10 May 1996; accepted in final form 19 September 1996. Hybertson, Brooks M., Stuart L. Bursten, Jonathan A. Leff, Young M. Lee, Eric K. Jepson, Chris R. Dewitt, John Zagorski, Hyun G. Cho, and John E. Repine. Lisofylline prevents leak, but not neutrophil accumulation, in lungs of rats given IL-1 intratracheally. J. Appl. Physiol. 82(1): 226-232, 1997. Interleukin-1 (IL-1) is increased in lung lavages from patients with the acute respiratory distress syndrome, and administering IL-1 intratracheally causes neutrophil accumulation and a neutrophil-dependent oxidative leak in lungs of rats. In the present study, we found that rats pretreated intraperitoneally with lisofylline [( R )-1-(5-hydroxyhexyl)-3,7-dimethylxanthine (LSF)], an inhibitor of lysophosphatidic acid acyl transferase, which reduces the production of unsaturated phosphatidic acid species, did not develop the lung leak or the related ultrastructural abnormalities that occur after intratracheal administration of IL-1. However, rats pretreated with LSF and then given IL-1 intratracheally did develop the same elevations of lung lavage cytokine-induced neutrophil chemoattractant (CINC) levels and the same increased numbers of lung lavage neutrophils as rats given IL-1 intratracheally. Lungs of rats given IL-1 intratracheally also had increased unsaturated phosphatidic acid and free acyl (linoleate, linolenate) concentrations compared with untreated rats, and these lipid responses were prevented by pretreatment with LSF. Our results reveal that LSF decreases lung leak and lung lipid alterations without decreasing neutrophil accumulation or lung lavage CINC increases in rats given IL-1 intratracheally. cytokines; cytokine-induced neutrophil chemoattractant; acute respiratory distress syndrome; inflammation; phosphatidic acid; acute lung injury 0161-7567/97 $5.00 Copyright © 1997 the American Physiological Society