15-hydroperoxy-5-8-11-13-eicosatetraenoic-acid and Asthma

Mast cells play a key role in the pathophysiology of asthma. These cells exert their effector functions by releasing a variety of proinflammatory and immunoregulatory compounds. Mast cells infiltrate the bronchial epithelium and smooth muscle to a higher degree in patients with asthma compared to control subjects. 15-Lipoxygenase type-1 (15-LO-1) is a prooxidant enzyme which is expressed in asthmatic lungs leading to formation of pro- and anti-inflammatory mediators. Here we report that interleukin-4 (IL-4) induced the expression of 15-LO-1 in human cord blood derived mast cells (CBMC) as demonstrated by RT-PCR, western blot and immunocytochemistry. The major metabolite of arachidonic acid formed via the 15-LO pathway in IL-4 treated CBMC was identified as 15-ketoeicosatetraenoic acid (15-KETE, also named 15-oxo-ETE) with smaller amounts of 15-hydroxyeicosatetraenoic acid (15-HETE) as identified by HPLC and mass spectrometry (MS/MS). Furthermore, immunohistochemical stainings demonstrated the expression of 15-LO-1 in mast cells in lung and skin in vivo. Osmotic activation of CBMC with mannitol resulted in activation of the 15-LO-1 pathway. In conclusion, the expression of 15-LO-1 and release of 15-LO-1 derived products by mast cells may contribute to the role of these cells in asthma and other inflammatory diseases.

Topics: Arachidonate 15-Lipoxygenase; Arachidonic Acids; Asthma; Fetal Blood; Humans; Hydroxyeicosatetraenoic Acids; Interleukin-4; Isoenzymes; Leukotrienes; Lipid Peroxides; Lung; Mannitol; Mast Cells; Skin; Tryptases

The precise mechanisms(s) responsible for airway hyperreactivity to spasmogenic agents (for example, cholinergic stimulants, alpha-adrenergic agonists, histamine, PGF2 alpha and several other nonspecific stimuli) in asthmatics is not known. Substantial evidence exists fo the mediator, as well as modulatory, roles of the products of arachidonic acid metabolism operating via the cyclo-oxygenase pathway in the pathophysiology of lung diseases. Aspirin and other inhibitors of cyclo-oxygenase induce severe bronchospasm and asthmatic attacks in a significant population of asthmatic patients. This adverse effect of aspirin is often attributed to inhibition of the synthesis and release of defensive "modulatory" endogenous prostaglandins (PGD and PGI2?) in the lungs. Thus, removal of their "negative feedback" mechanism on the allergic release of chemical mediators (e.g., histamine and SRS-A: leukotriene C and D) from lung mast cells could lead to an enhancement of the release of mediators and severity of asthmatic attacks. In addition to these mechanisms, recent work suggests the diversion of arachidonic acid (AA) metabolism via the lipoxygenase pathway (especially after cyclo-oxygenase inhibition by aspirin and indomethacin), thereby leading to the formation of a new class of biologically active lipids: hydroperoxy acids (HPETE and HETE), leukotrienes (LTA, B, C, D, E) and SRS or SRS-A (LTC, LTD). The inherent or drug (aspirin)-induced deficiency or blockade of cyclo-oxygenases(s) and/or peroxidases in the lungs (and/or other body tissues, including leukocytes) leading to diversion of AA into the formation and accumulation of SRS (leukotrienes), especially in sensitive individuals, could explain the mechanism of aspirin-induced asthma, and probably the generalized syndrome of aspirin-tolerance. Furthermore, the hydroperoxy acids, leukotrienes, (SRS) may also sensitize receptors for other mediators and common nonspecific irritants, and/or induce airway contractions directly. Collectively, these mechanisms could account for airway hyperreactivity in asthma.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonic Acids; Aspirin; Asthma; Autacoids; Humans; Leukotrienes; Lipid Peroxides; Lipoxygenase; Peroxides; Prostaglandin-Endoperoxide Synthases