prostaglandins: then and now and next
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DITORIAL
Prostaglandins: Then and Now and Next
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EARLY 75 YEARS ago, Drs Kurzrock andLieb (1), gynecologists at Columbia Univer-
ity College of Physicians and Surgeons, observedhat human myometrium exhibits rhythmic con-raction and relaxation when incubated with freshuman seminal fluid. Goldblatt (2) and von Euler3) each independently confirmed the findings, anddentified the active principle as an acidic lipid.elieving the lipid was produced in the prostateland, von Euler named it prosta glandin. Eliasson4) later showed that seminal fluid prostaglandinPG) in fact derives from the seminal vesicles. Hisore accurate label, “vesiglandin,” never did dis-
lace the misnomer we continue to use. Bergstromlater to earn a Nobel Prize for his effort along withir John Vane and Bengt Samuelsson) and Sjovall5) then determined that the active component inhe seminal fluid is not a single substance buteveral closely related compounds. Bergstrom’sroup isolated from homogenates of sheep vesic-lar glands 2 of the substances in crystalline formnd described their chemical structure (6). Theest, as they say, is history.
It is the oxygenation of several 20-carbon poly-nsaturated fatty acids (arachidonic, dihomogam-alinolenic, and eicosapentaenoic acids) in nearly
ll human cell types that results in the formation ofeveral classes of bioactive products termed eico-anoids (“eicosa” equals 20). These consist of PGsncluding prostacyclin and thromboxanes, leuko-rienes, and lipoxins, all of which play criticaloles in the regulation of immunity and inflam-ation, among other physiologic and pathologic
rocesses.The basic structure of PGs is that of a 20-carbon
atty acid with a 5-membered (cyclopentane) ringt C8 through C12. The alphabetical nomenclaturePGE, PGF, PGD) relates to the chemical architec-ure of the ring. For example, PGE and PGF differnly in the presence of a ketone or hydroxylunction at C9. A subscript numeral after the lettersndicates the degree of unsaturation in the fattycid side chains. The numeral 1 indicates the pres-nce of a double bond at C13-C14 (PGE1 from
ihomogammalinolenic acid), 2 marks the pres-eminars in Arthritis and Rheumatism, Vol 33, No 3 (December), 200
nce of an additional double bond at C5-C6 (PGE2
rom arachidonic acid), and 3 denotes a third dou-le bond at C17-C18 (PGE3 from eicosapentaenoiccid).
In this issue of Seminars, Martel-Pelletier et al7) focus their discussion on the role of PGE2 in theunction of joint tissues and on the newest thera-eutic advances deriving from an understanding ofatty-acid metabolism, namely selective inhibitionf cyclooxygenase (COX) 2. All of the PG precur-or fatty acids are substrates for both the COX-1nd the COX-2 isoforms. As Martel-Pelletier et al7) state, the COX enzyme system is complex.ndeed, the entire “arachidonic-acid cascade,”hich also leads to production of leukotrienes (via
ipoxygenases) and lipoxins (via sequential actionf 5 and 15 lipoxygenases, hence, lipoxins fromlipoxygenase-interaction products”), is exceed-ngly complex. It is a regulatory system designedor host defense. The role of eicosanoids in thenflammatory process is not as well defined as onceupposed, because the stable PGs PGE and PGI2
ave antiinflammatory and inflammatory effects8). PGJ (a metabolite of PGD) and lipoxins appearo act as brakes to protect against run-away inflam-atory responses. Even leukotriene B4 appears
apable of modulating inflammation and immuneesponses (9). Thus, it will take exquisitely selec-ive alteration of particular points in the systemeg, PG and thromboxane synthases, or eicosanoideceptors) to modify it to the advantage of the host.he coxibs are a good first step. As is often thease with new therapeutic agents that emerge from
From the Rheumatology Division, Department of Medicine,niversity of Massachusetts Medical School, Worchester, MA.Robert B. Zurier, MD: Professor of Medicine; Chief, Rheu-
atology Division, Department of Medicine, University of Mas-achusetts Medical School, Worcester, MA.
Address reprint requests to: Robert B. Zurier, MD, De-artment of Medicine, University of Massachusetts Medicalchool, 55 Lake Ave North, Worcester, MA 01655. e-mail:[email protected]© 2003 Elsevier Inc. All rights reserved.0049-0172/03/3303-0001$30.00/0
Rober
uriers
doi:10.1016/j.semarthrit.2003.09.001
1373: pp 137-139
superb and novel basic research, the clinical con-tribution gets a bit overblown. It is clear thatselective COX-2 inhibitors are equivalent in effi-cacy to the traditional nonsteroidal antiinflamma-tory drugs and reduce the more serious adverseupper gastrointestinal events (bleeding, ulcer, per-foration).
However, as Martel-Pelletier et al (7) indicate,biochemical evidence that selective COX-2 inhib-itors might promote thrombosis is supported bycase reports and clinical trials. For example, in theVIGOR trial, when comparing rofecoxib withnaproxen—in which aspirin could not be taken—a4-fold increase in the rate of myocardial infarction(MI) was observed with the use of the COX-2inhibitor (10). In the CLASS trial, which comparedcelecoxib with ibuprofen or diclofenac, the MI ratedid not differ between groups, but 20% of patientstook low-dose aspirin (11). An analysis by theauthors of the rofecoxib (VIGOR) trial found that4% of patients met clinical criteria for treatmentwith low-dose aspirin but did not take it, and thatsmall group of patients accounted for 38% of theMIs. Thus, it is important to determine risk ofcardiovascular events before beginning treatmentwith COX-2–selective inhibitors. It is likely thatthis tendency toward clotting is a drug-class effectand is not unique for 1 formulation of selectiveCOX-2 inhibitor. It is now known that COX-2 canbe up-regulated in stimulated human endothelialcells (12). Selective COX-2 inhibition results insuppression of PGI2 (prostacyclin) synthesis bythese cells. Because platelet thromboxane produc-tion is spared by selective COX-2 inhibition, theplatelet-vascular balance mediated between the ef-fects of thromboxane (platelet aggregation, vaso-constriction) and PGI2 (inhibition of platelet aggre-gation, vasodilation) is tilted toward promotion ofthrombosis.
Widespread use of the selective COX-2 inhibi-tors will no doubt help define the function of eachCOX isoform in health and disease. It is likely thatfurther effort will be directed toward developmentof agents that selectively suppress thromboxane, or
enhance prostacyclin, or reduce leukotriene B4.More specific inhibition of thromboxane actionmay become possible now that 2 thromboxanereceptors have been cloned and characterized (13).Attempts to modulate eicosanoid production alsohave been directed at providing fatty acids otherthan arachidonic acid as substrates for oxygenationenzymes in an effort to generate a unique antiin-flammatory eicosanoid profile. The fatty acidsthemselves, by virtue of their incorporation intosignal transduction elements, also influence thefunction of cells involved in inflammation andimmune responses in an eicosanoid independentmanner (14).
The biologic effects of compounds produced inthe lipoxygenase pathway indicate their impor-tance in inflammatory diseases. They are, in fact,the major mediators of inflammation formed by theoxygenation of arachidonic acid, and they are im-plicated as key mediators in several diseases, in-cluding inflammatory bowel disease, psoriasis,bronchial asthma, and rheumatoid arthritis. Ther-apy by virtue of lipoxygenase blockade has notbeen encouraging, but advances in this area areanticipated. Several leukotrienes increase prolifer-ation of fibroblasts when PG synthesis is inhibited(15), findings that emphasize the importance ofinteractions between the cyclooxygenase and li-poxygenase pathways and that suggest limitationsto traditional nonsteroidal antiinflammatory ther-apy.
Aspirin acetylation of COX-2 in endothelialcells suppresses PG synthesis but leads to genera-tion of lipoxins that serve to prevent leucocyte-mediated tissue injury (16). Lipoxins are not newkids on the block; their long evolutionary history isreflected in the fact that macrophages of rainbowtrout generate lipoxins rather than PGs or leukotri-enes. Enhancement of the antiinflammatory prop-erties of lipoxins by pharmaceutical means is verylikely in our future.
The overview by Martel-Pelletier et al (7) willstimulate new thought and further investigation.
REFERENCES1. Kurzrock R, Lieb CC. Biochemical studies of human
semen. II. The action of semen on the human uterus. Proc SocExp Biol Med 1930;28:268-71.
2. Goldblatt MW. A depressor substance in seminal fluid. JSoc Chem Ind 1933;52:1056-9.
3. von Euler US. On the specific vasodilating and plain
muscle stimulating substances from accessory genital glands inman and certain animals (prostaglandin and vesiglandin).J Physiol (London) 1936;88:213-19.
4. Eliasson R. Studies on prostaglandins: Occurrence, for-mation and biological actions. Acta Physiol Scand 1959;46(suppl 158):1-52.
138 ROBERT B. ZURIER
5. Bergstrom S, Sjovall J. The isolation of prostaglandin Efrom sheep prostate glands. Acta Chem Scand 1960;14:1701-6.
6. Bergstrom S, Ryhage R, Samuelsson B, Sjovall J. Thestructure of prostaglandin E1, F1, and F2. Acta Chem Scand1962;16:501-11.
7. Martel-Pelletier J, Pelletier J-P, Fahmi H, Cyclooxygen-ase 2 and prostaglandins in articular tissues. Semin ArthritisRheum 2003;3:155-67.
8. Zurier RB. Prostagland. In: Cunningham-Rundles S, ed.Nutrient Modulation of the Immune Response. New York:Marcel Dekker, 1993;201-22.
9. Haeggstrom JZ, Wetterholm A. Enzymes and recep-tors in the leukotriene cascade. Cell Mol Life Sci 2002;59:742-53.
10. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinaltoxicity of rofecoxib and naproxen in patients with rheumatoidarthritis. N Engl J Med 2000;343:1520-28.
11. Silverstein FE, Faich G, Goldstein JL, Simon LS, PincusT, Whelton A, et al. Gastrointestinal toxicity with celecoxib vsnonsteroidal anti-inflammatory drugs for osteoarthritis and
rheumatoid arthritis: The CLASS study. A randomized controltrial. Celecoxib Long-Term Arthritis Safety Study. JAMA2000;284:1247-55.
12. Caughey GE, Cleland LG, Penglis PS, Gamble JR,James MJ. Roles of cyclooxygenase (COX)-1 and COX-2 inprostanoid production by human endothelial cells: Selectiveup-regulation of prostacyclin synthesis by COX-2. J Immunol2001;167:2831-8.
13. Kinsella BT. Thromboxane A2 signaling in humans: A“Tail” of two receptors. Biochem Soc Trans 2001;29:641-54.
14. Zurier RB. Gammalinolenic acid treatment of rheuma-toid arthritis. In: Kremer JM, ed. Medicinal Fatty Acids inInflammation. Berlin: Birkhauser Verlag 1998;29-44.
15. Baud L, Perez J, Denis M, Ardaillous R. Modulation offibroblast proliferation by sulfidopeptide leukotrienes: Effect ofindomethacin. J Immunol 1987;138:1190-95.
16. Serhan CN. Lipoxins and aspirin-triggered 15 epi-li-poxin biosynthesis: An update and role in anti-inflammationand pro-resolution. Prostaglandins Other Lipid Mediat 2002;68-69:433-55.
139EDITORIAL