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Cyclo-oxygenase (COX), also known as prostaglandin H synthase (PGHS), is the rate limiting enzyme for the conversion of arachidonic acid to prostanoids and exists in two isoforms. COX-1 is constitutively expressed and is responsible for the basal production of prostanoids, whereas COX-2 is highly inducible by a number of stimuli including cytokines and is associated with inflammation. Accumulating evidence suggests that the induction and regulation of COX-2 may be key elements in the pathophysiological process of a number of inflammatory disorders and may play an important role in the pathogenesis of asthma.1
Bronchoalveolar lavage fluid from patients with symptomatic asthma contains significantly increased levels of a number of proinflammatory cytokines including interleukin 1β and tumour necrosis factor α.2 3 It has recently been shown that these proinflammatory cytokines are capable of inducing COX-2 in a number of cultured airway cells including airway epithelial cells,4 5 airway smooth muscle cells,6 7and airway fibroblasts.8 In addition, we have shown that transforming growth factor β1 and the proinflammatory asthmatic mediator bradykinin also induce COX-2 in human airway smooth muscle cells.9 10 These results suggest that COX-2 expression may be upregulated in asthmatic airways.
Several studies have examined COX-2 expression in asthmatic airways but the data are conflicting. Demoly et al 11 found that COX-2 was expressed in normal human respiratory epithelium and was not quantitatively upregulated in stable asthma. Conversely, Sousa and coworkers found increased expression of COX-2 in the epithelium and submucosa of asthmatic patients compared with control subjects.12 Similarly, Taha and colleagues reported greater COX-2 immunoreactivity in the induced sputum, the submucosal inflammatory infiltrate, and the airway epithelium of patients with asthma than of unaffected control subjects.13 Since corticosteroids have been shown in vitro to inhibit COX-2 expression in various airway cells,4-9the fact that the majority of asthmatic subjects in these studies were receiving treatment with inhaled corticosteroids at various doses may largely explain the discrepancies between these studies. In this issue of Thorax Redington et al 14 have made a fresh contribution to the study of COX-2 expression in asthma. Aware of the potential confounding effect of corticosteroids on COX-2 expression, they obtained bronchial biopsy specimens from three groups of subjects: atopic asthmatics treated with β2 agonists alone, atopic asthmatics additionally receiving regular treatment with corticosteroids, and non-asthmatic control subjects. They found that the expression of both COX-2 mRNA and immunoreactive protein was increased in the airway epithelium of non-steroid treated asthmatics compared with non-asthmatic control subjects, and that the expression of COX-2 in asthmatic subjects receiving regular treatment with corticosteroids was not significantly different from that observed in non-asthmatic controls. Their findings clearly demonstrate that COX-2 is upregulated in the airway epithelium of asthmatic subjects and downregulated by corticosteroid treatment, and further strengthen the hypothesis that COX-2 may play a major role in the pathogenesis of asthma.
Since we and others6 7 9 have shown that COX-2 is markedly induced in airway smooth muscle cells in vitro by proinflammatory cytokines and other mediators that exist in asthmatic airways, it is reasonable to speculate that COX-2 expression in airway smooth muscle is also upregulated in asthma. It would be important to study COX-2 expression in airway smooth muscle of asthmatic subjects as it is an important component of the airways and plays a crucial part in the pathophysiology of asthma.
The consequences of increased COX-2 expression in asthma are not clear. PGE2, the main product of COX-2 induction, is an important anti-inflammatory mediator which has considerable bronchoprotective effects in the airways.15 It is possible that PGE2 production as a result of COX-2 induction may exert a braking effect on the inflammatory process in asthmatic airways. However, PGE2 at higher concentrations also causes contraction of airway smooth muscle via thromboxane receptors.16 PGD2, PGF2α, and thromboxane A2 are also potent bronchoconstrictors via thromboxane receptors.16 17 PGI2 causes relaxation of isolated precontracted human bronchus12 but has little effect on airway calibre in vivo.18
Several studies of the effect of COX-2 induction on airway functions have been conducted. Gavett et al showed that allergen induced inflammation was increased in COX-2 deficient mice.19 Belvisi et al reported that PGE2 from COX-2 induction in airway smooth muscle inhibited cell proliferation.20 We found that PGE2 release after COX-2 induction mediated IL-1β and bradykinin induced attenuation of human airway smooth muscle cyclic AMP generation in response to β agonists,21 22 and that PGE2 from both COX-1 and COX-2 also largely mediated bradykinin stimulated IL-8 release from human airway smooth muscle cells.23 These results suggest that COX-2 induction exerts both protective and proinflammatory effects. The consequences of increased COX-2 expression in asthma are therefore likely to be complex and depend on the balance between the proinflammatory and the anti-inflammatory effects of prostanoids produced by various cell types under different circumstances. A better understanding of this issue might be achieved by direct functional studies with airway tissues from asthmatic patients, but these are notoriously difficult to obtain.
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