The Pivotal Role of 5-Lipoxygenase Products in the Reaction of Aspirin-sensitive Asthmatics to Aspirin

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Abstract
A subset of persons with asthma develop bronchospasm, naso-ocular, gastrointestinal, and/or dermal reactions after ingesting aspirin (ASA) or agents with the capacity to inhibit cyclooxygenase. The bronchopulmonary reactions have been associated with a rise in urinary LTE4. We examined the effects of an inhibitor of 5-lipoxygenase, zileuton, in a group of eight asthmatic patients with known sensitivity to ASA accompanied by LTE4 hyperexcretion. We first confirmed ASA sensitivity and an increase in urinary LTE4 after ASA ingestion in these patients using a placebo-controlled ASA challenge. Subjects were then randomized to a double-blind, crossover trial to examine the effects of zileuton versus placebo on the response to ASA. Zileuton treatment decreased baseline urinary LTE4 excretion from a mean of 469 ± 141 pg/mg creatinine to 137 ± 69 pg/mg creatinine (p < 0.02) and blunted the maximum increase in urinary LTE4 after ingestion of ASA (3,539 ± 826 pg/mg creatinine versus 1,120 ± 316 pg/mg creatinine [p< 0.01]). The pre-ASA challenge FEV1 was unchanged by zileuton (3.41 ± 0.15 L versus 3.35 ± 0.17 L, zileuton versus placebo). Zileuton prevented the fall in FEV1 in response to ingestion of ASA; post-ASA ingestion the mean of the minimal FEV1 fell to 2.72 ± 0.18 L on the placebo day while there was no significant fall on the zileuton day (3.26 ± 0.17 L; p < 0.014). Zileuton also prevented the development of the nasal, gastrointestinal (p < 0.006 and p < 0.025, respectively), and dermal symptoms which developed after ASA ingestion. Our data demonstrate that products of the 5-lipoxygenase pathway are critical mediators of the bronchospasm and associated end-organ events seen after ingestion of ASA in sensitive asthmatic patients.

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