Arachidonic acid metabolism in in¯ammatory cells of patients with bronchial asthma Over the last few years, the demonstration of bene®cial effects of leukotriene receptor antagonists in various forms of asthma has renewed clinical and pharmacologic interest in this class of lipid mediators. Several studies demonstrated an increased biosynthesis of cysteinyl leukotrienes (CysLT) in asthmatic patients. However, the reasons for the dysregulated production of CysLTs in asthmatic patients are not completely de®ned. An improved method of lipid mediator detection and the availability of cells isolated from human airways (by bronchoalveolar lavage [BAL] and bronchial biopsies) have allowed initial studies to address this issue. Eosinophils retrieved from in¯amed airways of asthmatics have a larger arachidonic acid (AA) content than their blood counterpart. The high level of AA in these cells is primarily due to a remodeling of endogenous arachidonate pools with the accumulation of this fatty acid in a triglyceride-associated pool. In addition, elevated levels of a secretory form of phospholipase A 2 , the key enzyme initiating the cascade of CysLTs, are found in the BAL of asthmatics. Finally, eosinophils isolated from the BAL of asthmatics have an increased expression of LTC 4 synthase. The level of expression of this enzyme correlates with the increased amount of CysLTs produced in the airways of these patients. Taken together, these data identify at least two possible mechanisms to explain the excessive CysLT production in asthmatics: 1) an increased content of AA in the glycerolipid pools of in¯ammatory cells 2) an enhanced activity of key biosynthetic enzymes involved in CysLT synthesis. C. Calabrese, M. Triggiani, G. Marone Division of Allergy and Clinical Immunology, University of Naples ``Federico II'', Naples, Italy G. Mazzarella Department of Respiratory Diseases, Second University of Naples, Naples, Italy Key words: airway in¯ammation; arachidonic acid; bronchial asthma. Massimo Triggiani, MD Division of Clinical Immunology and Allergy University of Naples, Federico II Via Pansini 5 I-80131 Naples Italy Tel. +39081 7462219 Fax: +39081 7462271 Email: triggian@unina.It Several clinical and experimental studies have empha- sized the role of chronic in¯ammation in the pathogen- esis of bronchial asthma. A large number of in¯ammatory mediators, including cytokines, lipid mediators, and enzymes, participate in the development of bronchial asthma, playing a role, often redundant, in the recruitment of in¯ammatory cells into the airways, and inducing bronchoconstriction and epithelium damage. Over the last few years, the results of clinical trials on leukotriene receptor antagonists in various forms of asthma have renewed the clinical and pharmacologic interest in this class of lipid mediators (l, 2). Furthermore, the introduction of bronchoalveo- lar lavage (BAL) and transbronchial biopsy procedures in patients with asthma, coupled with improved molecular and cellular biology techniques, has sub- stantially advanced our knowledge of the biochemistry of lipid mediators. Arachidonic acid (AA) represents only 5±10% of esteri®ed fatty acids of glycerolipids in human in¯ammatory cells, but it constitutes the only fatty acid capable of generating molecules (eicosanoids) that modulate, in a complex fashion, in¯ammatory and immune responses (3). Among eicosanoids, the cystei- nyl leukotrienes (CysLTs) probably represent the most important class of molecules in the pathogenesis of bronchial asthma (2). The initial step in the biosynthesis of CysLTs (LTC 4 , LTD 4 , and LTE 4 ) is the mobilization of arachidonic acid from cellular glycerolipids by various phospholipases A 2 (PLA 2 ) (4). Arachidonic acid is then transformed into the intermediate hydro- peroxide 5-HPETE and, subsequently, into LTA 4 by the same enzyme, 5-lipoxygenase (5-LO). LTA 4 is rapidly converted to LTC 4 in cells containing the enzyme LTC 4 synthase (predominantly mast cells, basophils, and eosinophils in man) (5). LTC 4 is the ®rst active metabolite in the CysLT cascade and the only one synthesized and secreted by in¯ammatory cells. In the extracellular environment, LTC 4 is subse- quently converted to LTD 4 and LTE 4 by a c-glutamyl transpeptidase and a dipeptidase, respectively (6). Allergy 2000: 55: Suppl 61: 27±30 Printed in UK. All rights reserved Copyright # Munksgaard 2000 ALLERGY ISSN 0108-1675 27