PGE2 is a powerful bronchodilator when given in aerosol form. Unfortunately, it also promotes coughing, and an analog that possesses only the bronchodilator properties has been difficult to obtain.
PGF2α and TXA2 are both strong bronchoconstrictors and were once thought to be primary mediators in asthma. Polymorphisms in the genes for PGD2 synthase, both DP receptors, and the TP receptor have been linked with asthma in humans. DP antagonists, particularly those directed against DP2, are being investigated as potential treatments for allergic diseases including asthma. However, the cysteinyl leukotrienes—LTC4, LTD4, and LTE4—probably dominate during asthmatic constriction of the airways. As described in Chapter 20, leukotriene-receptor inhibitors (eg, zafirlukast, montelukast) are effective in asthma. A lipoxygenase inhibitor (zileuton) has also been used in asthma but is not as popular as the receptor inhibitors. It remains unclear whether leukotrienes are partially responsible for acute respiratory distress syndrome.
Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells.
The word “cytoprotection” was coined to signify the remarkable protective effect of the E prostaglandins against peptic ulcers in animals at doses that do not reduce acid secretion. Since then, numerous experimental and clinical investigations have shown that the PGE compounds and their analogs protect against peptic ulcers produced by either steroids or NSAIDs. Misoprostol is an orally active synthetic analog of PGE1. The FDA-approved indication is for prevention of NSAID-induced peptic ulcers. This and other PGE analogs (eg, enprostil) are cytoprotective at low doses and inhibit gastric acid secretion at higher doses. Because it is also an abortifacient, misoprostol is a pregnancy category X drug. Misoprostol use is low, probably because of its adverse effects including abdominal discomfort and occasional diarrhea. Dose-dependent bone pain and hyperostosis have been described in patients with liver disease who were given long-term PGE treatment.
Selective COX-2 inhibitors were developed in an effort to spare gastric COX-1 so that the natural cytoprotection by locally synthesized PGE2 and PGI2 is undisturbed (see Chapter 36). However, this benefit is seen only with highly selective inhibitors and is offset, at least at a population level, by increased cardiovascular toxicity.
Cells of the immune system contribute substantially to eicosanoid biosynthesis during an immune reaction. T and B lymphocytes are not primary synthetic sources; however, they may supply arachidonic acid to monocyte-macrophages for eicosanoid synthesis. In addition, there is evidence for eicosanoid-mediated cell-cell interaction by platelets, erythrocytes, leukocytes, and endothelial cells.