Pediatric Pulmonology 18:129-134 (1994) zy Original zy Articles - Inhibitory Effects of Theophylline, Terbutaline, and Hydrocortisone on Leukotriene B, and C4 Generation by Human Leukocytes In Vitro T. Shimizu, MD,~ S. Kristjansson, MD,~ G. Wennergren, MD, PhD,l G.C. Hansson, MD, PhD,' and B. Strandvik, MD, PhD' Summary. Leukotriene B , (LTB,) and leukotriene C, (LTC,) are considered to be important mediators in the pathophysiology of asthma. Theophylline, terbutaline, and hydrocortisone are drugs commonly used in the treatment of asthma. In the present study we have investigatedthe in vitro inhibitory effects of theophylline, terbutaline, and hydrocortisone on LTB, and LTC, generation from human leukocytes.After preincubation in the presence of these drugs, the cells were stimulated with the calcium ionophore A 23187 and the supernatants were analyzed for their LTB, and LTC, content using reverse-phase high-performance liquid chromatography (HPLC). Total leukotriene (LT) production (the combined amounts of LTB, and LTC,) was dose-dependently inhibited by pretreatment with theophylline, terbutaline or hydrocortisone. Therapeutic levels of hydrocortisone (5 zyxwvutsr x zyxwvut M) inhibited LTB, and LTC, productionin an additive way, as did the combinationof hydrocortisone plus terbutaline (5 x M). A statistically significant effect of diminished LTB, generation was obtained after preincubationwith therapeutic levels of theophylline plus terbutaline, but no such effect was seen for LTC, levels. The in vitro inhibitory effects on LTB, and LTC, generation from human leuko- cytes by theophylline,terbutaline, and hydrocortisone, as well as the additive effect of hydrocorti- sone plus theophyllineor terbutaline, add to our understandingof the therapeutic effects of these drugs in the treatment of bronchopulmonary obstruction. Pediatr Pulmonol. 1994;18:129-134. M) plus theophylline (5 x 0 1994 Wiley-Liss, Inc. Key words: Calcium ionophore A 23187 stimulation, reverse-phase high-performance liquid chromatography. INTRODUCTION zyxwvutsrq Leukotriene B, (LTB,) and leukotriene zyxwvuts C, (LTC,) are membrane-derived mediators produced from arachidonic acid metabolites through the 5-lipoxygenase pathway and are considered to be important mediators in airway in- flammation and the pathophysiology of asthma (Fig. l).'32 LTC, and its metabolites, LTD, and LTE,, are potent bronchoconstrictor agents in normal and asthmatic subjects394 and are mainly generated by eosinophils. LTB, can be generated in vitro by neutrophils, mono- cytes, eosinophils, and mast cells;5 it is a potent chemo- tactic agent for neutrophils and eosinophils6 and may prolong and amplify the inflammatory phenomenon in asthmatic airways. zyxwvuts 73 Consequently, it has been sug- gested that 5-lipoxygenase inhibitors or leukotriene (LT) antagonists may be well suited as antiasthma drugs. Sev- eral clinical studies in asthmatic patients have recently shown the efficacy of such drugs."" Xanthines, P-receptor agonists, and corticosteroids have all been shown to inhibit LT biosynthesis. The xanthines and P-receptor agonists are thought to inhibit Received January 28, 1993; (revision) accepted for publication April 30, 1994. From the Departments of Pediatrics,' and Medical Biochemistry,* Goteborg University, Goteborg, Sweden. This work was supported by grants from the Swedish Medical Re- search Council (4995 and 7461), the Swedish Heart Lung Foundation and the Goteborg Mason Order Orphanage Foundation. Address correspondence and reprint requests to Dr. zyxw S. Kristjansson, Department of Pediatrics, Goteborg University, East Hospital, S-416 85 Goteborg, Sweden. Present address of T. Shimizu: Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan. 0 1994 Wiley-Liss, Inc.