PGE2 and PGI2 limit T-lymphocyte proliferation in vitro, as do corticosteroids. PGE2 also inhibits B-lymphocyte differentiation and the antigen-presenting function of myeloid-derived cells, suppressing the immune response. T-cell clonal expansion is attenuated through inhibition of interleukin-1 and interleukin-2 and class II antigen expression by macrophages or other antigen-presenting cells. The leukotrienes, TXA2, and platelet-activating factor stimulate T-cell clonal expansion. These compounds stimulate the formation of interleukin-1 and interleukin-2 as well as the expression of interleukin-2 receptors. The leukotrienes also promote interferon-γ release and can replace interleukin-2 as a stimulator of interferon-γ. PGD2 induces chemotaxis and migration of Th2 lymphocytes. These in vitro effects of the eicosanoids agree with in vivo findings in animals with acute organ transplant rejection.
A. Inflammation
Aspirin has been used to treat arthritis of all types for approximately 100 years, but its mechanism of action—inhibition of COX activity—was not discovered until 1971. COX-2 appears to be the form of the enzyme most associated with cells involved in the inflammatory process, although, as outlined above, COX-1 also contributes significantly to prostaglandin biosynthesis during inflammation. Aspirin and other anti-inflammatory agents that inhibit COX are discussed in Chapter 36.
B. Rheumatoid Arthritis
In rheumatoid arthritis, immune complexes are deposited in the affected joints, causing an inflammatory response that is amplified by eicosanoids. Lymphocytes and macrophages accumulate in the synovium, whereas leukocytes localize mainly in the synovial fluid.
The major eicosanoids produced by leukocytes are leukotrienes, which facilitate T-cell proliferation and act as chemoattractants. Human macrophages synthesize the COX products PGE2 and TXA2 and large amounts of leukotrienes.
Latanoprost, a stable long-acting PGF2α derivative, was the first prostanoid used for glaucoma. The success of latanoprost has stimulated development of similar prostanoids with ocular hypo-tensive effects, and bimatoprost, and travoprost are now available. These drugs act at the FP receptor and are administered as drops into the conjunctival sac once or twice daily. Adverse effects include irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis.
Bimatoprost is FDA approved for treatment of eyelash hypotrichosis and has shown efficacy in enhancing eyelash growth after chemotherapy. The drug is applied in a 0.03% solution to the skin at the base of the upper lashes. A common but minor adverse effect is darkening of eyelid skin due to increased melanin production that is reversible with discontinuation. Recent trials have also demonstrated efficacy in eyebrow hypotrichosis, and emerging studies have suggested that this drug may have utility for treating alopecia.