Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Whittle, Brendan J.R.; Higgs, G. A.; Eakins, Kenneth E.; Moncada, Salvador; Vane, John R.

doi:10.1038/284271a0

Cited by 383 publications

(124 citation statements)

References 14 publications

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“…A close correspondence of concentration-dependent inhibition of COX-2 mRNA and protein levels by sodium salicylate and aspirin is consistent with the interpretation that inhibition of COX-2 induction is elicited by salicylic acid. This finding explains why salicylate, although inactive in blocking COX-1 or COX-2 activity, is capable of inhibiting prostaglandin biosynthesis in intact cells and inflammatory exudates (7,15). By suppressing COX-2 induction, salicylate eliminates the robust PGE 2 synthesis induced by inflammatory mediators.…”

Section: Discussionmentioning

confidence: 66%

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

Sansores-García

Chen

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

275

194

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The pharmacological action of salicylate cannot be explained by its inhibition of cyclooxygenase (COX) activity. In this report, the effects of aspirin and sodium salicylate on COX-2 expressions in human umbilical vein endothelial cells and foreskin fibroblasts were evaluated. Aspirin and sodium salicylate at therapeutic concentrations equipotently blocked COX-2 mRNA and protein levels induced by interleukin-1␤ and phorbol 12-myristate 13-acetate. The suppressing effect was more pronounced in cultured cells deprived of fetal bovine serum for 24 h, suggesting that it may be cell cycle related. Salicylate inhibited nascent COX-2 transcript synthesis but had no effect on COX-2 mRNA stability. It inhibited COX-2 promoter activity in a concentration-dependent manner. In mice pretreated with aspirin (10 and 30 mg͞kg), followed by challenge with lipopolysaccharide, COX-2 mRNA expression in peritoneal macrophages was markedly suppressed. These findings suggest that salicylate exerts its antiinf lammatory action in part by suppressing COX-2 induction, thereby reducing the synthesis of proinf lammatory prostaglandins.Since the classic work of Vane (1), it has been widely accepted that the pharmacological action of nonsteroidal antiinflammatory drugs (NSAID) is mediated by inhibiting the activity of cyclooxygenase (COX), a key enzyme in biosynthesis of proinflammatory prostaglandins. Recent studies implicate COX-2 induction as a critical event in inflammation (2). This notion has been supported by effective suppression of inflammatory responses in experimental animals by selective COX-2 inhibitors (3, 4). Aspirin (acetylsalicylic acid) is a nonselective COX inhibitor (5, 6). Moreover, aspirin is rapidly deacetylated in blood to form salicylic acid. Salicylic acid has been a known NSAID for over a century, but its mechanism of action remains a pharmacological enigma. It has virtually no inhibitory activity against purified COX-1 or COX-2, although it inhibits prostaglandin synthesis in intact cells (7). To elucidate the mechanism by which salicylic acid exerts its antiinflammatory action, we evaluated the effects of aspirin and sodium salicylate on COX-2 expression in human umbilical vein endothelial cells (HUVEC) and human foreskin fibroblasts (HFF) induced by inflammatory mediators. We show here that aspirin and sodium salicylate at therapeutic concentrations suppress COX-2 gene transcription. When administered to mice pretreated with lipopolysaccharide, aspirin inhibited COX-2 mRNA levels in peritoneal macrophages. MATERIALS AND METHODSMaterials. Recombinant IL-1␤, phorbol 12-myristate 13-acetate (PMA), sodium salicylate, aspirin, NS398, indomethacin, and lipopolysaccharide (LPS) were obtained from Sigma.Cell Culture. HUVECs were cultured as described (8) in medium 199 containing 20% FBS, 50 g͞ml endothelium cell growth factor, 10 units͞ml heparin, 100 g͞ml streptomycin, and 100 units͞ml penicillin. Only first and second passage cells were used. HFFs were obtained from American Type Culture Collection and were cu...

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Section: Discussionmentioning

confidence: 66%

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

Sansores-García

Chen

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

275

194

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“…Although salicylate has been shown to be similarly potent as an analgesic and anti-inflammatory drug (Atkinson & Collier, 1980; Rainsford, 1984), it has almost no effect on prostanoid formation of gastric mucosa (Ligumsky et al, 1982;Whittle et al, 1980), macrophages (Kuehl et al, 1980), ram seminal vesicle microsomes (Humes et al, 1981), or thrombocytes (Roberts et al, 1984;Smith & Willis, 1971;Vargaftig, 1978a). Platelet function is not affected by salicylate as well (O'Brien, 1968;Roberts et al, 1984;Smith & Willis, 1971;Weiss et al, 1968;Zucker & Peterson, 1970).…”

Section: Introductionmentioning

confidence: 99%

Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man.

Rosenkranz¹,

Fischer²,

Meese³

et al. 1986

Brit J Clinical Pharma

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The present study was designed to investigate the effects of salicylate on the antiplatelet action of acetylsalicylic acid as well as on in vivo prostanoid formation and platelet function in healthy volunteers. In the first study six female volunteers received 350 mg acetylsalicylic acid intravenously, with and without previous oral administration of sodium salicylate (1200 mg daily for 3 days). Urinary prostanoid excretion as well as platelet aggregation and thromboxane formation were measured before and during salicylate and after acetylsalicylic acid. In the second study seven female volunteers received sodium salicylate (52.6 mg kg‐1) or acetylsalicylic acid (60.7 mg kg‐1) for 8 days in a randomized cross‐over protocol. Urinary prostanoid excretion, platelet aggregation and thromboxane formation as well as salicylate plasma concentrations were determined before, during and after administration of each drug. Sodium salicylate did not impair the complete suppression of arachidonic acid‐induced platelet thromboxane formation and aggregation obtained by the single intravenous dose of acetylsalicylic acid in the first study. Sodium salicylate in the second study did not affect urinary excretion of prostaglandin E2, its major urinary metabolite (7 alpha‐hydroxy‐5,11‐ diketo‐tetranor‐prostane‐1,16‐dioic acid), and 2,3‐dinor‐6‐keto‐ prostaglandin F1 alpha, the main urinary metabolite of epoprostenol (prostacyclin, PGI2). In contrast, acetylsalicylic acid significantly decreased excretion rates of these prostanoids by 64, 59 and 61%, respectively. In both studies platelet aggregation and thromboxane formation induced by collagen, thrombin or arachidonic acid were not significantly affected by salicylate administration, whereas acetylsalicylic acid inhibited platelet aggregation induced by all three agents as well as thrombin‐ and arachidonic acid induced thromboxane formation.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Moreover, sodium salicylate was found to be ogenic in rats (Glenn et al, 1979;Whittle et al, gastroprotective against various noxious agents including ethanol (Robert, 1981). The mechanism of 1 Present address: Nattermann & Cie.…”

Section: Introductionmentioning

confidence: 99%

Effects of non‐steroidal anti‐inflammatory drugs on rat gastric mucosal leukotriene C₄ and prostanoid release: relation to ethanol‐induced injury

Peskar

Hoppe

Lange

et al. 1988

British J Pharmacology

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1 The effects of oral and subcutaneous administration of the non-steroidal anti-inflammatory drugs sodium salicylate, aspirin and indomethacin on ex vivo gastric mucosal release of leukotriene C4 (LTC4) prostaglandin E2 (PGE2), 6-oxo-PGFl, and thromboxane B2 (TXB2) were investigated in rats under basal conditions as well as after challenge with ethanol. 2 Basal release of PGE2, 6-oxo-PGF 1. and TXB2 was inhibited by oral administration of aspirin (0.6-400 mg kg-1) and indomethacin (4 or 20 mg kg-1), but not by sodium salicylate (up to 400mg kg-1), in a dose-dependent manner. Oral administration of aspirin in the dose range 3.2-400mgkg-' and of indomethacin (20mgkg-1) additionally inhibited release of LTC4, while sodium salicylate (up to 400mg kg -1) had no effect. Indomethacin (20mg kg-1) and aspirin (400mgkg-1) administered subcutaneously inhibited generation of cyclo-oxygenase products of arachidonate metabolism, but did not significantly affect LTC4 synthesis. 3 Oral instillation of ethanol caused gastric mucosal damage and simultaneously induced a selective increase in the ex vivo release of LTC4 from rat gastric mucosa, while release of cyclooxygenase products of arachidonate metabolism was not significantly affected. Oral pretreatment of rats with sodium salicylate protected the gastric mucosa and simultaneously inhibited the ethanolstimulated gastric mucosal LTC4 release in a dose-dependent manner. Sodium salicylate had no effects on the release of PGE2 and TXB2, while that of 6-oxo-PGFe was slightly increased. 4 Pretreatment with indomethacin (4 or 20mg kg-p.o.) or aspirin in doses up to 25mg kg-1 p.o. prior to oral instillation of ethanol did not inhibit gastric mucosal damage and had no effect on the stimulatory action of ethanol on LTC4 release. Higher doses of aspirin (100mgkg-1 or 400mgkg-1 p.o.) reduced the mucosal damaging effect of ethanol and simultaneously inhibited LTC4 release.5 The results suggest that aspirin and indomethacin in concentrations higher than those necessary to inhibit the cyclo-oxygenase pathway of arachidonate metabolism additionally inhibit gastric mucosal LTC4 synthesis under basal conditions, while sodium salicylate has no such effect. On the other hand, sodium salicylate, but not indomethacin or low doses of aspirin (up to 25mg kg 1), by an unknown mechanism inhibits stimulation of LTC4 biosynthesis by ethanol and simultaneously protects the gastric mucosa against ethanol-induced damage. Similar effects of high oral doses (> 100mgkg-1) of aspirin might be due to significant formation of salicylate. These results suggest that there is a causal relationship between enhanced LTC4 biosynthesis and the development of ethanol-induced gastric injury.

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Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Cited by 383 publications

References 14 publications

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man.

Effects of non‐steroidal anti‐inflammatory drugs on rat gastric mucosal leukotriene C₄ and prostanoid release: relation to ethanol‐induced injury

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Selective inhibition of prostaglandin production in inflammatory exudates and gastric mucosa

Cited by 383 publications

References 14 publications

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate

Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man.

Effects of non‐steroidal anti‐inflammatory drugs on rat gastric mucosal leukotriene C4 and prostanoid release: relation to ethanol‐induced injury

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Effects of non‐steroidal anti‐inflammatory drugs on rat gastric mucosal leukotriene C₄ and prostanoid release: relation to ethanol‐induced injury