Role of expression of prostaglandin synthases 1 and 2 and leukotriene C4 synthase in aspirin-intolerant asthma: a theoretical study

Altered expressions of the key enzymes in arachidonic acid (AA) metabolism, prostaglandin synthase 1 and 2 and cysteinyl leukotriene C-4 synthase, are of importance in understanding aspirin-induced asthma. We propose a mathematical model of AA metabolism and its interaction with non-steroidal anti-inflammatory drugs (NSAIDs). Model simulations depict the impact of modified expressions of the above enzymes on the time dependent synthesis of cysteinyl leukotrienes and anti-inflammatory prostaglandins before and during NSAID exposure in different model states describing healthy humans as well as aspirin-tolerant and -intolerant asthmatics. The results are compared and evaluated with experimental data taken from the literature. Our results identify the decreased expression of prostaglandin H synthase 1 and increased expression of leukotriene C-4 synthase as the key elements in AA metabolism that contribute to increased leukotriene C-4 and decreased anti-inflammatory prostaglandins after NSAID dosing in aspirin-intolerant patients. On the other hand, the decreased expression of prostaglandin H synthase 2 implies permanently increased leukotriene C-4 and lowers the sensitivity to increased drug doses. The model is used for identification of susceptible patient populations for aspirin and ibuprofen, and for identification of critical aspirin doses that might induce bronchoconstriction.