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Thorax 2000;55 (Suppl 2):S3–S9 S3

Aspirin and other anti-inflammatory drugs Thorax: first published as 10.1136/thorax.55.suppl_2.S3 on 1 October 2000. Downloaded from

Sir John Vane

Historical introduction inhibiting COX, thereby reducing prosta- , the active substance in plants glandin formation, providing a unifying expla- used for thousands of years as medicaments, nation for their therapeutic actions and their was synthesised by Kolbe in Germany in 1874. side eVects. This also firmly established certain MacLagan1 and Stricker2 showed that it was as important mediators of eVective in rheumatic . A few years later inflammatory disease (see reviews by Vane and salicylate was also in use as a treatment Botting7 and Vane et al8). COX first cyclises for chronic rheumatoid and as to form (PG) well as an compound. G2 and the peroxidase part of the then Felix HoVman was a young chemist working reduces PGG2 to PGH2. at . Legend has it that his father, who was taking salicylic acid to treat his arthritis, Discovery of COX-2 complained to his son about its bitter taste. Over the next 20 years several groups postu- Felix responded by adding an to lated the existence of isoforms of COX. Then salicylic acid to make acetylsalicylic acid. Rosen et al,9 studying COX in epithelial cells Heinrich Dreser, the Company’s head of phar- from the trachea, found an increase in activity macology, showed it to be , anti- of COX during prolonged . This 3 pyretic, and anti-inflammatory. Bayer intro- increase in activity was not accounted for by an duced the new drug as “” in 1899 and increase in the known mRNA of 2.8 kb. They sales have increased ever since. found a second mRNA of 4.0 kb and suggested In the latter part of the 20th century several that this was derived from a distinct COX- other non-steroidal anti-inflammatory drugs related gene which encoded for a protein with (NSAIDs) were discovered, including antipy- COX activity. Needleman and his group10–12 rine, , and, more reported that bacterial lipopolysaccharide recently, the fenamates, indomethacin and (LPS) increased the synthesis of prostaglandins . Despite the diversity of their chemi- in human monocytes and in mouse cal structures, these drugs all share the same peritoneal macrophages in vivo. This increase, therapeutic properties. They alleviate the but not the basal level of enzyme, was inhibited swelling, redness and of inflammation, by dexamethasone and associated with de novo reduce a general fever, and cure a . synthesis of new COX protein. This gave rise to They also share, but not equally, a number of the concept of “constitutive” and “inducible” side eVects including damage to the gastric forms of COX. http://thorax.bmj.com/ mucosa, delay in the birth process, and damage The breakthrough came from molecular to the . A particularly interesting “side biologists outside the field of prostaglandins. eVect”, now used prophylactically, is the Simmons et al,13 studying neoplastic transfor- anti-thrombotic eVect. Many clinical trials mation, discovered a second form of COX have shown that aspirin given once a day in induced by v-src, serum, or phorbol in doses as low as 75 mg will help to prevent heart chicken embryo cells.13 14 It was encoded by a attacks or . 4.1 kb mRNA similar in size to that reported When a chemically diverse group of drugs by Rosen et al.9 They cloned the gene, deduced on October 1, 2021 by guest. Protected copyright. shares not only the same therapeutic qualities the protein structure, and found it homologous (which in themselves have not much connec- to COX but to no other known protein. tion with each other), but also the same side Herschman and colleagues15 independently eVects, it is a fairly safe bet that their actions are found a similar gene in the mouse, as did Sim- based on a single biochemical intervention. For mons et al,16 O’Banion et al,17 and Sirois and many years pharmacologists and biochemists Richards.18 searched for such a common mode of action COX-1 and COX-2 have molecular weights without finding one that was satisfactory. of 71 kd and a 60% homology. Glucocorticoids It was against this background that, using a inhibit the expression of COX-2 and this is an crude preparation of prostaglandin synthase additional aspect of their anti-inflammatory (now known as cyclo-oxygenase or COX), action. The levels of COX-2, normally very low Vane4 found a dose dependent inhibition of in cells, are tightly controlled by a number of prostaglandin formation by aspirin, salicylate, factors including cytokines, intracellular mes- and indomethacin but not by . Two sengers, and by the availability of substrate. other reports from the same laboratory lent 5 support to his findings. Smith and Willis COX-1 The William Harvey showed that aspirin prevented the release of COX-1 has three folding units: an epidermal Research Institute, prostaglandins from aggregating human plate- growth factor-like domain, a membrane bind- London EC1 6BQ, UK lets and Ferreira et al6 demonstrated that ing section, and an enzymatic domain. The JRVane aspirin-like drugs blocked prostaglandin re- sites for peroxidase and cyclo-oxygenase activ- Correspondence to: lease from the perfused, isolated spleen of the ity are adjacent but spatially distinct. The Sir John Vane dog. Vane4 proposed that all NSAIDs act by enzyme integrates into only a single leaflet of

www.thoraxjnl.com S4 Vane

the membrane bilayer and thus the muscle cells, pulmonary endothelial cells, and Thorax: first published as 10.1136/thorax.55.suppl_2.S3 on 1 October 2000. Downloaded from position of the COX channel allows arachi- alveolar macrophages treated with LPS or donic acid to gain access to the active site from proinflammatory cytokines. In the carrageenin the interior of the bilayer.19 induced pleurisy model of inflammation, levels NSAIDs compete with arachidonic acid for of COX-2 protein increased maximally at two binding to the active site, thereby excluding hours in the cell pellets of pleural exudate.27 access for the substrate.20 Uniquely, aspirin However, lung tissue can also express COX-2 irreversibly inhibits COX-1 by of constitutively. COX-2 mRNA is weakly ex- serine 530. COX-1 has clear physiological pressed in unstimulated rat isolated perfused functions. Its activation leads, for instance, to lungs and is upregulated by nitric oxide (NO) the production of which, when donors.28 Human lungs obtained from accident released by the endothelium is victims29 and human cultured pulmonary anti-thrombogenic,21 and when released by the epithelial cells expressed more constitutive gastric mucosa is cytoprotective.22 COX-2 than constitutive COX-1.30 31 Interest- ingly, hypoxia induces COX-2 gene expression COX-2 in isolated perfused lungs of the rat without The structure of COX-223 closely resembles aVecting the mRNA for COX-1.28 This induc- that of COX-1 but, fortunately for the medici- tion of the COX-2 gene by hypoxia was inhib- nal chemist, the binding site for arachidonic ited by NO donors, which may represent one of acid (the COX channel) is slightly diVerent. the mechanisms of the beneficial eVect of The active site of COX-2 is a little larger and inhaled NO in pulmonary . can accommodate bigger structures than that Inflammatory stimuli cause diVerential re- of COX-1. A secondary internal pocket lease of prostaglandins from various regions of contributes significantly to the larger volume of the lungs. Human cultured pulmonary epithe- the active site of COX-2, although the central lial cells stimulated with LPS, interleukin (IL)- channel is also 17% bigger. 1á, tumour necrosis factor (TNF)á,ora

Since COX-2 is induced by inflammatory mixture of cytokines synthesise mainly PGE2

stimuli and by cytokines in migratory and other together with smaller amounts of PGF2á, PGI2,

cells, it is attractive to suggest that the and TXA2. This prostaglandin production can anti-inflammatory actions of NSAIDs result be suppressed by dexamethasone32 which indi- from the inhibition of COX-2, whereas the cates that it is caused by COX-2. unwanted side eVects such as damage to the Pollutants such as those in car exhausts can lining are caused by inhibition of the also induce COX-2 in human cultured airway constitutive enzyme, COX-1. This general epithelial cells, resulting in an increased forma- 33 concept is now widely accepted. tion of PGE2 and PGF2á. PGE2 and TXB2,in addition to COX-2 protein, could be detected Functions of COX-1 and COX-2 in the inflammatory exudate produced by LUNGS injection of carrageenin into the rat pleural Prostacyclin is a potent vasodilator of the pul- cavity.34 Thus, it seems likely that COX-2 is monary circulation in humans and other upregulated in the inflamed lungs of asthmatic http://thorax.bmj.com/ species. This endothelium derived prostacyclin patients resulting in increased production of is well placed to function as a local vasodilator bronchoconstrictor prostaglandins which exert and to prevent the formation of micro- an exaggerated eVect on the bronchiolar thrombi.24 smooth muscle that has become hyperreactive Pulmonary blood vessels are constricted by to constrictor agents.

PGF2á and (TX) A2 but, in some

species, they are dilated by PGE2. The ENDOTHELIUM

vasoconstrictor responses to PGF2á are potenti- Endothelial cells generate prostacyclin which is on October 1, 2021 by guest. Protected copyright. ated by hypoxia. Mediators of inflammation anti-aggregatory and a vasodilator. They such as bradykinin, histamine, and clearly contain COX-1 but McAdam et al35 and 5-hydroxytryptamine all release prostaglandins Catella-Lawson et al,36 using the selective

from lung tissue. Histamine releases PGF2á COX-2 inhibitors or in

from human lung fragments by stimulating H1 volunteers, found that the urinary of receptors. The lungs of asthmatic subjects pro- the prostacyclin metabolite was substantially duce more histamine than normal lungs, which suppressed by anti-inflammatory doses of correlates with the greater number of mast cells either drug. Thus, in the endothelium prosta- found in asthmatic lungs.25 cyclin is mainly produced by COX-2, probably The airways of most species, including induced by laminar shear stress.37

humans, are constricted by PGF2á, TXA2,

PGD2, and PGI2 whereas PGE2 is weakly bronchodilator. Asthmatic subjects are 8000 The “cytoprotective” action of prostaglandins times more sensitive to the bronchoconstrictor in preventing gastric erosions and ulceration is

action of inhaled PGF2á than healthy subjects. mainly brought about by endogenously pro-

COX-2 expression in airways has been re- duced prostacyclin and PGE2 which reduce viewed by Barnes et al.26 Airway hyperreactiv- gastric acid secretion, exert a direct vasodilator ity, a feature of allergic , is associated action on the vessels of the gastric mucosa, and with inflammation of the airways. There is stimulate the secretion of viscous mucus and increased expression of COX-2 mRNA and of duodenal bicarbonate.38 In most species, in- enzyme protein with no change in COX-1 lev- cluding humans, the protective prostaglandins els in pulmonary epithelial cells, airway smooth are synthesised by COX-1, although COX-2

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39 has been reported in the normal rat stomach, activity. Intense nerve stimulation, leading to Thorax: first published as 10.1136/thorax.55.suppl_2.S3 on 1 October 2000. Downloaded from in human gastric mucosa infected with Helico- seizures, induces COX-2 mRNA in discrete bacter pylori,40 and in ulcerative colitis.41 COX-2 neurones of the hippocampus,53 whereas acute is also expressed around the periphery of stress raises levels in the cerebral cortex. gastric ulcers in mice and rats. It may be COX-2 mRNA is also constitutively expressed involved in wound healing.42–44 Large quantities in the spinal cord of normal rats and may be of COX-2 are expressed in experimentally involved with processing of nociceptive induced and in human colon .45 46 stimuli.54

Endogenous fever producing PGE2 is KIDNEY thought to originate from COX-2 induced by Maintenance of kidney function both in animal LPS or IL-1 in endothelial cells lining the models of disease states and in patients with blood vessels of the hypothalamus.52 Li et al55 congestive heart failure, cirrhosis, or renal tested the eVects of LPS in producing a fever in

insuYciency is dependent on vasodilator pros- knockout mice. Wild type mice and COX-1(+/–)

taglandins. These patients are therefore at risk and COX-1(–/–) mice all responded to LPS with of renal ischaemia when prostaglandin synthe- a1°C rise in core temperature within one hour:

sis is reduced by NSAIDs. Synthesis of PGE2 the fever gradually abated over the next four

and prostacyclin is mainly by COX-1, although hours. By contrast, COX-2(+/–) and COX-2(–/–) there are discrete cells in the macula densa that mice displayed no temperature rise after LPS. contain constitutive COX-2.47 48 Prostacyclin Thus, COX-2 is necessary for LPS induced made by COX-2 may drive the renin- fever production. A corollary of this finding is system48; Schneider and Stahl49 that there is unlikely to be a COX-3 through have reviewed this rapidly evolving field. which brings down a fever. The Mice that lack the gene for production of selective COX-2 inhibitor rofecoxib is a potent COX-1 appear to be healthy and do not show agent in man.56 significant signs of kidney disease. This is in accord with the finding that inhibition of REPRODUCTIVE SYSTEM COX-1 by NSAIDs does not materially alter Expression of COX-1 is much greater than that renal function under normal physiological of COX-2 in the fetal heart, kidneys, lungs, and conditions, although a small percentage of brain, as well as in the decidual lining of the those taking NSAIDs have mild fluid retention. uterus.57 58 Prostaglandins synthesised by However, Morham et al reported that the COX-1 are apparently essential for the survival kidneys failed to develop fully after birth in of fetuses during parturition, since the majority COX-2(–/–) null mice, with the result that the of oVspring born to homozygous COX-1 animals died before they were eight weeks old.50 knockout mice do not survive.59 This high More recently, after some backcrossing of the mortality may result from the premature same COX-2(–/–) deficient mice in a diVerent closure of the ductus arteriosus. Female laboratory, a breed of COX-2(–/–) mice has been COX-2 knockout mice are mostly infertile, achieved which has little or no kidney malfunc-

producing very few oVspring because of a http://thorax.bmj.com/ tion and which live for three years.51 reduction in ovulation.60 COX-2 induction is Fitzgerald’s group36 compared the renal involved in ovulation and is clearly the trigger eVects of the non-selective COX inhibitor 61 62 for parturition, leading to PGF2á release to indomethacin with those of the COX-2 inhibi- cause contractions of the uterine smooth tor rofecoxib and with in healthy older muscle. adults over two weeks. Both active regimes were associated with a transient but significant decline in urinary sodium excretion during the Selective inhibition of COX-2 An estimated 34–46% of patients on chronic

first 72 hours. The glomerular filtration rate on October 1, 2021 by guest. Protected copyright. (GFR) was decreased by indomethacin but not NSAID treatment will have some form of changed significantly by rofecoxib. Thus, acute gastrointestinal adverse event. In the USA sodium retention by NSAIDs in healthy adults some 100 000 patients on NSAIDs are admit- is mediated by inhibition of COX-2, whereas ted to hospital each year because of perfora- depression of GFR is caused by inhibition of tions, ulcers, or in the stomach COX-1. (PUBs).63 Some 15% of these patients die in intensive care. Of course, these hospital admis- CENTRAL NERVOUS SYSTEM sions only represent the extreme of gastric irri- COX-1 is found in neurones throughout the tation, which ranges from mild dyspepsia all brain but it is most abundant in the forebrain the way through to PUBs. Even , rec- where prostaglandins may be involved in com- ognised as one of the mildest gastric irritants, plex integrative functions such as control of the causes problems in a significant proportion of autonomic nervous system and in sensory patients. Clearly, there is a dramatic need for processing. COX-2 mRNA is induced in brain anti-inflammatory drugs that do not aVect the tissue and in cultured glial cells by pyrogenic stomach. substances such as LPS, IL-1, or TNF.52 How- ever, low levels of COX-2 protein and COX-2 COX-2/COX-1 RATIOS mRNA have been detected in neurones of the The importance of the discovery of inducible forebrain without previous stimulation by COX-2 is highlighted by the diVerences in proinflammatory stimuli. These “basal” levels pharmacology of the two .64 Aspirin, of COX-2 are particularly high in neonates and indomethacin, and ibuprofen are much less are probably induced by physiological nervous active against COX-2 than against COX-1.65

www.thoraxjnl.com S6 Vane

Indeed, the strongest inhibitors of COX-1 such intestinal toxicity. These drugs have a much Thorax: first published as 10.1136/thorax.55.suppl_2.S3 on 1 October 2000. Downloaded from as aspirin, indomethacin, and are the higher potency against COX-1 than against NSAIDs that cause the most damage to the COX-2.7 Thus, when epidemiological results stomach. are compared with COX-2/COX-1 ratios, There are now many methods for measuring there is a parallel relationship between gastro- COX-2/COX-1 ratios, varying from human intestinal side eVects and COX-2/COX-1 enzyme assays in vitro66 to assays in human ratios. blood samples.67–69 In general, the whole blood The conclusion that inhibition of COX-1 assays are reproducible from laboratory to accounts for the gastric toxicity of NSAIDs is 69 laboratory and provide conditions that ap- strongly reinforced by the work of Warner et al proach the physiological. For instance, any in whole blood assays. They measured the of the drug will eVects of some 30 non-selective, selective, and highly selective COX-2 inhibitors in two types automatically be taken into account. of whole blood assay for COX-1 and COX-2 Implicit in the theory that COX-2 causes (fig 1). There is substantial evidence that inflammation is that NSAIDs are used in NSAIDs and COX-2 inhibitors have their inflammation because they inhibit COX-2. maximum anti-inflammatory eVect when The range of activities of NSAIDs against COX-2 is inhibited by about 80%. Figure 2 COX-1 compared with COX-2 explains the shows the eVects of these drugs on COX-1 at variations in the side eVects of NSAIDs at their the 80% inhibitory concentration for COX-2. anti-inflammatory doses. Garcia Rodriguez The NSAIDs that damage the stomach 70 and Jick have published a comparison of epi- strongly inhibit COX-1. demiological data on the side eVects of NSAIDs. Piroxicam and indomethacin in anti- Selective inhibition of COX-2 inflammatory doses showed high gastro- , , and were identified in the 1980s as potent anti- _3 inflammatory drugs with low ulcerogenic activity in the rat stomach. In some instances this was also shown to parallel low activity

_ Rofecoxib 2 against prostaglandin synthesis in the rat stom-

Etodolac ach. After the discovery of COX-2 these three Meloxicam _1 Celecoxib drugs were each found to be selective COX-2 Nimesulide

Meclofenamate inhibitors. Tomoxiprol Piroxicam Meloxicam is about 10 times more potent on 0 COX-2 than on COX-1 in the human whole blood assay. It is marketed around the world for use in and . 1 In double blind trials in many thousands of ratio (WHMA COX-2/COX-1)] Aspirin

Ibuprofen patients with osteoarthritis meloxicam pro- 80 http://thorax.bmj.com/ Naproxen 2 duced significantly fewer gastrointestinal ad- 71 72

Indomethacin verse eVects than the standard NSAIDs. log [IC

Suprofen Perforations, ulcerations, and oc- 5–50 3 curred in fewer meloxicam treated patients fold than in those treated with piroxicam, di- COX-2 < > 5-fold COX-2 selective 50-fold COX-2 clofenac, or naproxen. The frequency of selective selective adverse events with meloxicam was signifi- Figure 1 Activity in modified whole blood assay of various NSAIDs on COX-1 at a dose cantly less than with piroxicam and naproxen that gives an 80% inhibition of COX-2. Those below the line have selectivity towards 73 74

(p<0.05). on October 1, 2021 by guest. Protected copyright. COX-1 and these are grouped with others that have a less than fivefold selectivity towards COX-2. The next group contains meloxicam, etodolac, celecoxib, and nimesulide which Etodolac is marketed for the treatment of have 5–50 fold selectivity towards COX-2. Only rofecoxib has a greater than 50-fold osteoarthritis and rheumatoid arthritis. It is selectivity for COX-2. Modified from Warner et al.69 about 15 times more potent on COX-2 than on COX-1 in human whole blood. In healthy 100 human volunteers etodolac twice daily did not suppress gastric mucosal prostaglandin pro- 80 duction and caused less gastric damage than naproxen.75 Patients with osteoarthritis or 60 rheumatoid arthritis obtained relief from symptoms with etodolac equal to other com- 40 monly used NSAIDs, but with a lower incidence of serious gastrointestinal toxicity.76 20 Nimesulide is about 10 times more active on

COX-2 inhibited by 80% COX-2 than on COX-1 in the human whole % inhibition of COX-1 when 0 blood assay. In limited clinical trials in acute

DFP and chronic inflammation it was more eVective Aspirin NS-398 than placebo or had comparable anti- Etodolac Tolmetin Diflunisal Ketorolac L-745,337 Ibuprofen Celecoxib Naproxen Rofecoxib Piroxicam Diclofenac Ampyrone Zomepirac Meloxicam Ketoprofen Nimesulide

Fenoprofen inflammatory activity to established NSAIDs. Tomoxiprol Flurbiprofen Niflumic acid Indomethacin Interestingly, nimesulide seems safe to use in Meclofenamate Sodium salicylate

Sulindac sulphide aspirin sensitive asthmatic patients. Several Figure 2 Degree of inhibition of COX-1 in the whole blood assay plotted at concentrations recent studies in NSAID intolerant asthmatic of the drugs that give an inhibition of 80% of COX-2. patients have shown that therapeutic doses of

www.thoraxjnl.com Aspirin and other anti-inflammatory drugs S7

nimesulide did not induce asthmatic attacks COLON Thorax: first published as 10.1136/thorax.55.suppl_2.S3 on 1 October 2000. Downloaded from while high doses of 400 mg only precipitated Epidemiological studies have established a mild asthma in 10% of patients.77 Perhaps strong link between ingestion of aspirin and a aspirin induced asthma is associated with reduced risk of developing colon cancer.86 87 COX-1 inhibition? Sulindac also caused reduction of prosta- glandin synthesis and regression of adenoma- Inhibitors designed to act on COX-2 tous polyps in 11 of 15 patients with familial Needleman and his group at /Searle adenomatous polyposis (FAP), a condition in have made inhibitors that are some 1000 times which many colorectal polyps develop sponta- more potent against COX-2 than against neously with eventual progression to tumours. COX-1 in enzyme assays.78 One of these, Interestingly, COX-2 and not COX-1 is highly SC-58635 (celecoxib), is an eVective analgesic expressed in human and animal colon cancer for moderate to severe pain following tooth cells as well as in human colorectal adenocarci- extraction.79 Celecoxib given for seven days to nomas.45 46 In the mutant Apc mouse, which is human volunteers provided no evidence of a model of FAP in humans, the spontaneous gastric damage.80 Interestingly, in our whole development of intestinal polyposis was blood assay69 celecoxib is only 10 times more strongly reduced either by deletion of the active against COX-2 than COX-1, which is a COX-2 gene or by treatment with a selective comparable selectivity to meloxicam. COX-2 inhibitor.88–90 Nimesulide also reduced Celecoxib was launched in December 1998 the number and size of intestinal polyps in Min for the treatment of osteoarthritis and rheuma- mice.91 The development of azoxymethane toid arthritis. Extensive results induced colon tumours over a year was have not yet been published. Interestingly, inhibited in rats fed celecoxib.92 Thus, it is although doses up to 800 mg of celecoxib do highly likely that COX-2 inhibitors could be not aVect aggregation in volunteers, used prophylactically to prevent colon cancer there was an inhibition of serum thromboxane in genetically susceptible individuals without

B2 production of up to 70%, albeit with a shal- causing gastrointestinal damage themselves. low dose-response curve.35 Merck is also launching worldwide a COX-2 ALZHEIMER’S DISEASE inhibitor, rofecoxib or Vioxx. In phase I studies The connection between COX and a single dose of 250 mg daily for seven days Alzheimer’s disease has been based mostly on (which is 10 times the anti-inflammatory dose) epidemiology because of the lack of an animal produced no adverse eVects on the stomach model of the disease. A number of studies have mucosa, as evidenced by gastroscopy.81 After a shown a significantly reduced odds ratio for single dose of 1 g there was no evidence of Alzheimer’s disease in those taking NSAIDs as COX-1 inhibition in , but activity of anti-inflammatory .93–95 The Baltimore COX-2 in LPS stimulated monocytes ex vivo Longitudinal Study of Ageing96 with 1686 par- was reduced. For postoperative dental pain ticipants showed that the risk of developing rofecoxib at 25–500 mg showed equal analge- Alzheimer’s disease was reduced among users sic activity to ibuprofen82 and provided relief of NSAIDs, especially those who had taken the http://thorax.bmj.com/ from symptoms in a six week study of for two years or more. No osteoarthritis.83 Rofecoxib is also eVective at decreased risk was evident with paracetamol or 50 mg once daily in the pain of dysmenor- aspirin use. However, aspirin was probably rhoea. taken in a dose too low to have an anti- inflammatory eVect. The protective eVect of Other possible therapeutic uses for NSAIDs is consistent with evidence of inflam- selective COX-2 inhibitors matory activity in the pathophysiology of

PREMATURE LABOUR Alzheimer’s disease. There is a strong interest on October 1, 2021 by guest. Protected copyright. Prostaglandins are the cause of uterine con- in COX-2 in Alzheimer’s disease, and Pasinetti tractions during labour. NSAIDs such as and Aisen97 have shown expression of COX-2 indomethacin will delay premature labour by in the frontal cortex of the brain from these inhibiting the production of prostaglandins, patients. but will at the same time cause early closure of the ductus arteriosus and reduce urine produc- Conclusions tion by the fetal kidneys.84 The delay in the The identification of selective inhibitors of birth process is probably the result of inhibition COX-2 will clearly provide important advances of COX-2 since mRNA for COX-2 increases in the treatment of inflammation. Conven- substantially in the amnion and placenta tional NSAIDs lead to gastrointestinal side immediately before and after the start of eVects which include ulceration of the stom- labour,58 whereas the side eVects on the fetus ach, sometimes with subsequent perforation are caused by inhibition of COX-1. One cause and deaths estimated at several thousand a year of preterm labour could be an intrauterine in the USA alone. The evidence is strong, both infection resulting in release of endogenous from animal tests and from the clinic, that factors that increase prostaglandin production selective COX-2 inhibitors will have greatly by upregulating COX-2.85 Nimesulide reduces reduced side eVects. prostaglandin synthesis in isolated fetal mem- It is now becoming generally accepted that branes and has been used successfully for a the unwanted side eVects of NSAIDs result prolonged period to delay premature labour from their ability to inhibit COX-1 whilst their without manifesting the side eVects of in- anti-inflammatory (therapeutic) eVects result domethacin on the fetus.84 from inhibition of COX-2. This concept is now

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set in stone. Thus, selective COX-2 inhibitors Vane JR, eds. Eicosonoids, aspirin and asthma. New York: Thorax: first published as 10.1136/thorax.55.suppl_2.S3 on 1 October 2000. Downloaded from Marcel Dekker, 1998: 111–23. will provide an important advance in anti- 27 Tomlinson A, Appleton I, Moore AR, et al. Cyclo-oxygenase inflammatory treatment. In addition to their and nitric oxide synthase isoforms in rat carrageenin- induced pleurisy. Br J Pharmacol 1994;113:693–4. beneficial actions in inflammatory diseases, 28 Chida M, Voelkel NF. EVects of acute and chronic hypoxia these drugs may be useful in the future for the on rat lung . Am J Physiol 1996;270:L872– 8. prevention of colon cancer, Alzheimer’s dis- 29 O’Neill GP, Ford-Hutchinson AW.Expression of mRNA for ease, or premature labour. cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993;330:156–60. Finally, there are exciting clues to suggest 30 Asano K, Lilly CM, Drazen JM. Prostaglandin G/H that aspirin induced asthma may be a COX-1 synthase-2 is the constitutive and dominant isoform in cul- dependent eVect. If so, the selective COX-2 tured human lung epithelial cells. Am J Physiol 1996;271: L126–31. inhibitors may well avoid this distressing com- 31 Walenga RW, Kester M, Coroneos E, et al. Constitutive plication of treatment with NSAIDs. expression of prostaglandin endoperoxide G/H synthase (PGHS)-2 but not PGHS-1 in human tracheal epithelial cells in vitro. Prostaglandins 1996;52:341–59. 32 Mitchell JA, Belvisi MG, Akarasereenont P, et al. Induction 1 MacLagan TJ. The treatment of acute rheumatism by of cyclo-oxygenase-2 by cytokines in human pulmonary . Lancet 1876;i:342, 383. epithelial cells: regulation by dexamethasone. Br J Pharma- 2 Stricker S. Abstract in Dublin J Med Sci 52:395–396. Berlin col 1994;113:1008–14. Klin Wochenschr 1876;13:1–2, 15–16, 99–103. 33 Samet JM, Reed W, Ghio AJ, et al. Induction of 3 Dreser H. Pharmacologisches über Aspirin (Acetylsalicyl- prostaglandin H synthase 2 in human airway epithelial cells saüre). Pflüger’s Arch Gesamte Physiol Menschen Tiere 1899: exposed to residual oil fly ash. Toxicol Appl Pharmacol 1996; 76:306–18. 141:159–68. 4 Vane JR. Inhibition of prostaglandin synthesis as a 34 Harada Y, Hatanaka K, Kawamura M, et al. Role of prosta- mechanism of action for aspirin-like drugs. Nature New glandin H synthase-2 in formation in rat Biology 1971;231:232–5. carrageenin-induced pleurisy. Prostaglandins 1996;51:19– 5 Smith JH, Willis AL. Aspirin selectively inhibits prosta- 33. glandin production in human platelets. Nature 1971;231: 35 McAdam BF, Catella-Lawson F, Mardini IA, et al. Systemic 235–7. of prostacyclin by cyclooxygenase (COX)-2: 6 Ferreira SH, Moncada S, Vane JR. Indomethacin and aspi- the human pharmacology of a selective inhibitors of rin abolish prostaglandin release from spleen. Nature 1971; COX-2. Proc Natl Acad Sci 1999;96:272–7. :237–9. 231 36 Catella-Lawson F, McAdam B, Morrison BW, et al.EVects 7 Vane JR, Botting RM. Mechanism of action of aspirin-like of specific inhibition of cyclooxygenase-2 on sodium drugs. Semin Arthritis Rheum 1997;26:2–10 balance, hemodynamics, and vasoactive eicosanoids. 8 Vane JR, Bakhle YS, Botting RM. 1 and 2. J Pharmacol Exp Ther 1999;289:735–41. Ann Rev Pharmacol Toxicol 1998;38:97–120. 37 Topper JN, Cai J, Falb D, et al. Identification of vascular 9 Rosen GD, Birkenmeier TM, Raz A, et al. Identification of a cyclooxygenase-related gene and its potential role in endothelial genes diVerentially responsive to fluid mechani- prostaglandin formation. cal stimuli: cyclooxygenase-2, manganese superoxide dis- Biochem Biophys Res Commun mutase, and endothelial cell nitric oxide synthase are selec- 1989;164:1358–65. 10 Raz A, Wyche A, Needleman P. Temporal and pharmaco- tively up-regulated by steady laminar shear stress. 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