Too many COX (cyclo-oxygenase) spoil the broth: aspirin-sensitive asthma and 5-lypoxygenase
Authors: J. A. Mitchell, M. G. Belvisi
Journal: Thorax (1997)

This Editorial was initially submitted in 1995 to Thorax that occur in asthma.Indeed, the report by Sousa et al 10 as a hypothesis driven article.Nevertheless, at the time it in the current issue of Thorax confirms that COX-2 is was thought to be too controversial and unsubstantiated present in asthmatic tissue.Why then are NSAIDs unby any scientific evidence.However, with the publication successful in the treatment of asthmatic symptoms?Moreby the journal of Sousa's work showing that COX-2 is over, in a subpopulation of asthmatic subjects aspirin increased in asthmatic airways, our original hypothesis is actually causes asthma typified by generalised flush, ocular better supported.The potential for COX-2 in asthma and and nasal congestion, and an acute (often severe) asthmatic aspirin-sensitive asthma is discussed below.attack.These patients also appear to have an increased Constitutive COX-1 or inducible COX-2 convert number of COX-2 expressing mast cells. 10The answer to arachidonic acid to prostaglandins, thromboxanes, and this question may lie in the biochemical processes that prostacyclin (prostanoids).Prostanoids have both prooccur in this group of "aspirin-sensitive" asthmatic subtective properties -for example, in the gastric mucosajects.To date, aspirin-sensitive asthma has been attributed, and inflammatory properties.Indeed, non-steroidal antiat least in part, to the shunting of arachidonic acid from inflammatory drugs (NSAIDs) such as aspirin inhibit the COX pathway to the 5-lipoxygenase (5-LO) pathway both COX-1 and COX-2 1 resulting in therapeutic (antiresulting in the production of leukotrienes. 11 The "shunting inflammatory and analgesic) and deleterious (gastric ulcers hypothesis" has been an attractive one as leukotrienes and kidney failure) effects.Traditional NSAIDs such as contribute to allergic and inflammatory reactions by several aspirin tend to display COX-1 selectivity, 1 2 raising the mechanisms including constriction of smooth muscle and speculation that COX-1 inhibition is responsible for stimulation of airway mucus production.In addition, intheir well described side effects.This has recently been creased levels of leukotrienes have been detected in the strengthened by reports demonstrating that selective inurine of sensitive patients after aspirin.However, aspirinhibitors of COX-2 are anti-inflammatory without being tolerant asthmatics do not produce more leukotrienes after ulcerogenic. 2The induction of COX-2 in lung structures inhibition of the COX pathway, calling into question the may be of particular importance since prostaglandin E 2 validity of the "shunting hypothesis". 12 We would like to put modulates various pulmonary functions including airway forward an alternative hypothesis to explain how aspirinand vascular tone, plasma exudation, inflammatory cell sensitive asthma is initiated.recruitment and activity, cytokine release, mucus secretion, We hypothesise that, in sensitive patients, COX-2 preand cholinergic and sensory nerve function. 3ominates and is modified biochemically by aspirin, blocking the normal prostanoid profile and facilitating the Scientific basis production of 5-LO products (fig 1).This hypothesis is The induction of COX-2 in the lung may occur either supported by recent evidence showing that aspirin is, inlocally in pulmonary structures after airway damage, for deed, able to modify the products formed by purified example, resulting in an increase in cytokines (fig 1).COX-COX-2. 13 In the presence of aspirin COX-2, but not COX-2 may also be induced in lung tissues after cytokines are 1, is modified to form 15-HETE (normally a 15-LO elevated, as part of a systemic response to infection (fig metabolite 2 ).Furthermore, the normal metabolites of 1).Indeed, we and others have shown that COX-2 is COX-2 and all the metabolites of COX-1 are blocked by induced by inflammatory cytokines in different human aspirin.Consequently, in patients where COX-2 prepulmonary cells including airway epithelium, 4 airway dominates these observations would suggest that, in the smooth muscle, 5 6 lung macrophages and activated leucopresence of aspirin, arachidonic acid is still utilised by cytes. 2 With the wide range of effects produced by pro-COX and the metabolites merely diverted.stanoids it is surprising that NSAIDs do not have more How then can the "COX-2 hypothesis" explain the therapeutic uses in lung diseases.However, NSAIDs have apparent involvement of leukotrienes in aspirin-sensitive been useful in the treatment of cough induced by angioasthma?Recently Cla `ria and Serhan 14 showed that endotensin converting enzyme inhibitors. 7These studies thelial cells treated to express COX-2 produced 15-HETE illustrate the known modulatory action of prostanoids in the presence of aspirin which, in turn, was metabolised on sensory nerve function resulting in sensitisation of by 5-LO in associated neutrophils forming a group of novel the cough reflex. 8etabolites known as the 15-epilipoxins. 14However, the functional consequences of the production of these compounds remains unknown.We have shown that various Therapeutic potential airway cells can be induced to express COX-2 and We would suggest that, as in other organs, 9 lung tissues express COX-2 during inflammatory events such as those that, under these conditions, the normal conversion of on July 25, 2023 by guest.