Novel 5-Lipoxygenase Inhibitors in Inflammation and Asthma
The discovery of mammalian lipoxygenases which convert arachidonic acid to oxygenated products with potent inflammatory and anaphylactic properties has led to growing speculation that these enzymes are central to certain disease processes (Samuelsson, 1983; Higgs, Moncada and Vane, 1984). This speculation has been supported by the demonstration of lipoxygenase activity in a number of different tissues following stimulation. For example, pulmonary tissues synthesize the peptido-leukotrienes (LTC4, D4 and E4), which are products of 5-lipoxygenase, in response to immunological challenge. These leukotrienes comprise the activity originally referred to as ‘slow reacting substance of anaphylaxis’ (SRSA), they are powerful constrictors of airway smooth muscle and are thought to be mediators of anaphylactic bronchoconstriction. Phagocytic leukocytes also convert arachidonic acid to leukotrienes and the major product in polymorphonuclear leukocytes (PMNs) is the di-hydroxy acid LTB4. Leukotriene B4, along with some of the mono-hydroxy lipoxygenase products is chemotactic and it has been suggested that LTB4 production by activated PMNs represents a local control mechanism for the accumulation of leukocytes at inflammatory sites.
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