Chronic cough is one of the commonest respiratory symptoms. Cough has been considered to be a defense mechanism of the airway to remove irritant particles or excess mucus, whereas non-productive cough, which is not associated with the clearance of the tracheobronchial mucus, may occur via increased cough reflex sensitivity. Inflammatory mediators such as prostaglandins may adjust the cough reflex sensitivity. However, little is known about how cough reflex sensitivity is influenced by airway inflammatory processes. Although our previous study has clearly shown that arachidonate cyclooxygenase products can modulate airway cough reflex sensitivity to inhaled capsaicin 1, the effects of other mediators remains unknown.

It has been recognized that prostaglandin I2 (PGI2, prostacyclin) is the most abundant prostanoid generated on IgE-dependent challenge of human lung tissue in vitro 23. Others reported that alveolar macrophages are able to synthesize large amount of PGI2 4. These findings indicate that PGI2 may play some role in the asthmatic airway and can affect airway cough reflex sensitivity. This study was conducted to elucidate this hypothesis. We investigated the effect of oral administration of beraprost, a chemically and biologically stable analog of PGI2 {sodium (±)-4[(1R, 2R, 3aS, 8bS)-1, 2, 3a, 8b-tetrahydro-2-hydroxyl 2[(3S, 4RS)-3-hydroxy-4-methyl-oct-6-yne-(E)-l-enyl]-5-cyclopenta [b] benzofuranyl] butyrate}, on cough reflex sensitivity to inhaled capsaicin in patients with stable asthma 5.

Cough threshold to inhaled capsaicin before each treatment (run-in, washout) and after treatment with beraprost and placebo are shown in Figure 2. Geometric mean values for the cough threshold were 29.5 (GSEM 1.17) μM in the run-in period, 26.5 (GSEM 1.18) μM in the washout period, 17.8 (GSEM 1.20) μM after beraprost treatment and 30.3 (GSEM 1.21) μM after placebo treatment. The cough threshold after the beraprost treatment was significantly (p < 0.05) lower than the value after the placebo treatment. FVC, FEV1 or MMF value was not significantly different between run-in period, washout period, beraprost treatment and placebo treatment as shown in Table 2.

Figure 3 and figure 4 show the changes in serum IgE and peripheral blood eosinophils, respectively. Treatment with beraprost did not affect the IgE production or peripheral blood eosinophil count.

The present study showed that two-week treatment with a stable PGI2 analogue, beraprost, decreased the cough threshold to inhaled capsaicin in asthmatic patients. No difference could be found in the baseline pulmonary function, IgE production or peripheral eosinophil count between beraprost and placebo treatments. These findings suggest that PGI2 enhances the cough reflex sensitivity in the asthmatic airway.

Cough is one of the main symptoms of bronchial asthma which can profoundly and adversely affect the quality of patient's lives and social activities, whereas the mechanisms underlying the cough remain obscure. Previous researchers 12 indicated that cough receptors are stimulated by local bronchoconstriction. This finding may be one of the causes of cough in bronchial asthma. However, recent studies about cough variant asthma (CVA) revealed normal baseline pulmonary function and mild bronchial hyperresponsiveness 1314. Our previous study has also demonstrated that inhaled procaterol in a dose sufficient to produce bronchodilation has no effect on airway cough receptor sensitivity in asthma 15. O'Connell and colleagues have reported that cough reflex sensitivity is increased in some asthmatic patients suffering from daily coughing and recovers to normal range after relief of the cough on treatment 16. These findings suggest that cough reflex hypersensitivity is another mechanism of chronic non-productive cough in asthma, in addition to cough receptor stimulation by local bronchoconstriction 12.

It has been revealed that inflammatory mediators such as arachidonate metabolites play major roles in the pathogenesis of bronchial asthma, however, the relationship between inflammatory mediators and airway cough reflex sensitivity remains obscure. Some studies indicated that some inflammatory mediators might modulate the sensitivity of cough reflex 117. We showed that intrinsic thromboxane A2 (TxA2) is a possible modulator augmenting both airway cough reflex sensitivity and bronchial responsiveness while it does not have bronchoconstricting effect in stable asthmatics 11819. Other researchers reported that prostaglandin F2α (PGF2α) enhances airway cough reflex sensitivity with bronchoconstricting effect 220. It has been also shown that inhaled prostaglandin E2 (PGE2), which acts as a bronchodilator, enhances cough reflex sensitivity 2021. Although cysteinyl leukotrienes (cLTs) play an important role in bronchomotor tone of the asthmatic airway, their role in cough reflex sensitivity is controversial 1922. These findings indicate that arachidonate metabolites including prostaglandins may have variable roles in the local control of the cough reflex with no relation to bronchoconstriction.

It has been known that PGI2 is the most abundant prostanoid generated on IgE-dependent challenge of human lung tissue in vitro 23. Others reported that alveolar macrophages are able to synthesize a large amount of PGI2 4. These findings imply that PGI2 plays some role in asthmatic airway. Although PGI2 causes relaxation of isolated precontracted human bronchus 23, its clinical effect is limited: short-term protection against immediate bronchoconstriction provoked by exercise 24, and nebulized distilled water 24 but not by allergen 25 or aspirin 26. Therefore, the exact role of PGI2 in asthmatic airway remains obscure. Hardy et al. reported an irritative effect of single inhalation of PGI2 on human airways 27, but influence of repeated administration has not been studied. Szczeklik and their colleagues also reported that four out of twelve asthmatic patients complained of coughing during PGI2 inhalation 28. However, these previous reports have not investigated the change of cough reflex sensitivity. Thus the exact role of PGI2 in airway cough reflex sensitivity also remains unknown. We observed that some patients complained of coughing on treatment with beraprost but none did with placebo. The implication of this study is that PGI2 may be involved in the pathogenesis of cough reflex sensitivity rather than bronchodilation and it may explain the role of PGI2 in the asthmatic airway which has been unknown so far.

Overall, our data support the conclusion that inhibition of PGI2 formation or action may be a novel treatment for chronic non-productive cough in asthmatic airway, especially in cough variant asthma or cough predominant asthma with normal baseline pulmonary function. This is the first report demonstrating the role of PGI2 in cough reflex sensitivity in the asthmatic airway. Further studies may be required to elucidate the role of PGI2 in other eosinophilic bronchial disorders presenting with non-productive cough with normal baseline pulmonary functions 293031.

cLT = cysteinyl leukotriene; CVA = cough variant asthma; FEV1 = forced expiratory volume in one second; FVC = forced vital capacity; GSEM = geometric standard error of the mean; PGE2 = prostaglandin E2; PGF2α = prostaglandin F2α; PGI2 = prostaglandin I2; MMF = maximal mid expiratory flow; TxA2 = thromboxane A2.