Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma.
Over the last few years, the demonstration of beneficial 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 defined. 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 inflamed 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 A2, 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 LTC4 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 inflammatory cells 2) an enhanced activity of key biosynthetic enzymes involved in CysLT synthesis.
Calabrese
C
C
Division of Allergy and Clinical Immunology, University of Naples Federico II, Italy.
Triggiani
M
M
Marone
G
G
Mazzarella
G
G
D016718:Arachidonic Acid / Q000378:metabolism*; D001249:Asthma / Q000276:immunology* / Q000378:metabolism*; D003545:Cysteine / Q000096:biosynthesis; D004804:Eosinophils / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D054501:Group II Phospholipases A2; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis; D008168:Lung / Q000276:immunology*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2
D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D016718:Arachidonic Acid; D005982:Glutathione Transferase; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; C041116:leukotriene-C4 synthase; D003545:Cysteine