Prostaglandins in inflammation and disease

Prostaglandins (PGs) were first linked with inflammation in studies showing that the mechanical irritation of rabbit eyes released a mediator, labeled 'irin', into the anterior chamber of the eye. Irin was later identified as a mixture ofPGE 2 and PGF2o (Ref 1). It is now recognized that any process leading to membrane disruption also leads to the release of PG. Carrageenan produces an acute inflammation when injected into the footpad of the rat and this model has been used extensively in the study of inflammation. Experi- ments using carrageenan have been credited with the dis- covery of indometacin (a cyclo-oxygenase inhibitor) and the identification of histamine, 5-hyclroxytryptamine (5-HT), the kinins, and the PGs as active elements in inflammation. Evidence has accumulated that the various oxidation products ofarachadonic acid are involved in producing all of the cardinal signs of inflammation. Vasodilatation (and thus redness) is caused by the release into the tissues of prostacyclin (PGIz), PGEI, PGE2, PGD2, and throm- boxane (Tx)A~. The effects of these compounds are an- tagonized to a certain degree by the vasoconstrictive activity of the endoperoxides and PGF2~ (Ref 2). While only weakly active in producing swelling, PGG2, PGH2, PGI2, PGE and PGF contribute synergistically to edema formation by bradykinin and histamine 3. The role of PG in the induction of fever is at present unclear. Whereas arachadonic acid itself is pyrogenic, the known PG deri- vatives are by themselves not capable of causing fever. However, the non-steroidal anti-inflammatory agents such as indometacin drugs which interfere with PG syn- thesis, are antipyretic. It is thought, therefore, that some unknown derivatives of arachadonic acid are mediators of fever 3. Pain is also produced in inflammatory models by arachadonic acid, and by PGE 1 and PGE 2 in synergistic way with bradykinin and histamin&. The fifth cardinal sign of inflammation is loss of function and PG-mediated inhibition of cellular activity during inflammatory and immune responses is very clear. While PGs along with other mediators help to 'drive' Department of Surgery, University of California, San Diego, LaJolla, CA 92093, USA. inflammatory reactions of all types, they are more impor- tant in some types of inflammation than in others. Their major role in the sunburn reaction, for example, is irrefutable. The early stages of sunburn can be completely reversed by the topical application of the cyclo-oxygenase inhibitor, indometacin +. It appears that the later stages of the sunburn response are promoted by mediators released by infiltrating leukocytes and PG seem to function in this inflammatory process by affecting the metabolism of these cells as well. The presence of PGE2, for example, is particularly related to the release of histamine 4. As a general rule, prostaglandins of the E series potentiate the actions of proinflammatory mediators, while prostaglandins of the F series counteract these effects 4. The leukotrienes, arachadonic acid derivatives produced as a result of lipoxygenase activity, are undoubtedly also major participants in inflammation but discussion of these compounds is beyond the scope of this review.