The source of thromboxane and prostaglandins in experimental inflammation

Higgs, G. A.; Moncada, Salvador; Salmon, John A.; Seager, Kaye

doi:10.1111/j.1476-5381.1983.tb10530.x

Cited by 115 publications

(52 citation statements)

References 20 publications

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“…Importantly, we have shown that TXA 2 was produced significantly earlier than PGE 2 . This has been observed in fresh, nonadherent human monocytes (G.E.C., unpublished data); adherent human monocytes (24); and murine macrophages (25) as well as in animal models of inflammation (26). As was the case with exogenous AA, this finding also supports the proposal that TXA synthase, compared with PGE synthase, has a greater affinity for PGH 2 , whether the latter is synthesised from endogenous or exogenous AA.…”

Section: Discussionsupporting

confidence: 73%

Differential Regulation of Prostaglandin E2 and Thromboxane A2 Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors

Penglis

Cleland

Demasi

et al. 2000

The Journal of Immunology

102

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There is an autocrine relationship between eicosanoid and cytokine synthesis, with the ratio of prostaglandin E2 (PGE2)/thromboxane A2 (TXA2) being one of the determinants of the level of cytokine synthesis. In monocytes, cyclooxygenase type 1 (COX-1) activity appears to favor TXA2 production and COX-2 activity appears to favor PGE2 production. This has led to speculation regarding possible linkage of COX isozymes with PGE and TXA synthase. We have studied the kinetics of PGE2 and TXA2 synthesis under conditions that rely on COX-1 or -2 activity. With small amounts of endogenously generated prostaglandin H2 (PGH2), TXA2 synthesis was greater than PGE2. With greater amounts of endogenously generated PGH2, PGE2 synthesis was greater than TXA2. Also, TXA synthase was saturated at lower substrate concentrations than PGE synthase. This pattern was observed irrespective of whether PGH2 was produced by COX-1 or COX-2 or whether it was added directly. Furthermore, the inhibition of eicosanoid production by the action of nonsteroidal anti-inflammatory drugs or by the prevention of COX-2 induction with the p38 mitogen-activated protein kinase inhibitor SKF86002 was greater for PGE2 than for TXA2. It is proposed that different kinetics of PGE synthase and TXA synthase account for the patterns of production of these eicosanoids in monocytes under a variety of experimental conditions. These properties provide an alternative explanation to notional linkage or compartmentalization of COX-1 or -2 with the respective terminal synthases and that therapeutically induced changes in eicosanoid ratios toward predominance of TXA2 may have unwanted effects in long-term anti-inflammatory and anti-arthritic therapy.

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Section: Discussionsupporting

confidence: 73%

Differential Regulation of Prostaglandin E2 and Thromboxane A2 Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors

Penglis

Cleland

Demasi

et al. 2000

The Journal of Immunology

102

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“…In the sponge model of inflammation, TXB2 is produced by migrating leukocytes and platelets do not contribute to TXB2 concentrations in the exudates (21). The similar potency of aspirin and salicylate in reducing TXB2 and PGE2 concentrations in inflammatory exudates suggests that the effects of both drugs are due to salicylate accumulating at the inflammatory site.…”

Section: Discussionmentioning

confidence: 82%

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Higgs¹,

Salmon²,

Henderson³

et al. 1987

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

202

109

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Among the nonsteroid antiinflammatory drugs there is generally a close correlation between the potency of their inhibition of arachidonate cyclooxygenase, and thus prostaglandin production, and their antiinflammatory activity.One anomaly in this generalization is that whereas aspirin and salicylate are equipotent as antiinflammatory agents, salicylate is less active than aspirin in inhibiting prostaglandin production in vitro. Using rats, we have now measured the concentrations of aspirin and salicylate in plasma and in inflammatory exudates after their oral administration and determined their effects on thromboxane B2 production in clotting blood and prostaglandin (PG) E2 concentrations in the exudates. We have also investigated the effects of both drugs, at concentrations achieved in the exudates, on PGE2 production by nonproliferative explants of acutely inflamed tissues. Aspirin is rapidly metabolized, resulting in peak concentrations of salicylate in the plasma and exudate that exceeded peak concentrations of aspirin by 30-to 50-fold. Furthermore, concentrations of aspirin rapidly declined, whereas high concentrations of salicylate persisted in the plasma and in the exudate for up to 6 hr after a single administration of aspirin. Both drugs reduced PGE2 concentrations in inflammatory exudates by 50-70%, but aspirin was considerably more potent than salicylate in inhibiting thromboxane B2 production in clotting blood. The concentration of salicylate found in inflammatory exudates 6 hr after the administration of aspirin was sufficient to reduce PGE2 production in explants by more than 50%. We conclude that the antiinflammatory action of both drugs depends on the inhibition of PGE2 synthesis by salicylate.The discovery that aspirin, indomethacin, and salicylate inhibit the synthesis of prostaglandins (1-3) provided the first comprehensive explanation of the mechanism of action of these drugs. Subsequent studies have shown that the broad group of nonsteroid antiinflammatory drugs inhibits arachidonate cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandin endoperoxides (for review see ref. 4). However, anomalies exist in the potencies of these drugs with respect to their antiinflammatory activities and to their ability to inhibit cyclooxygenase; of particular interest has been the disparity between the potency of aspirin and salicylate in inhibiting cyclooxygenase. Aspirin and salicylate are equipotent as antiinflammatory agents, but aspirin is some 20 times more potent than salicylate in inhibiting an enzyme preparation from guinea pig lung in vitro (1). Furthermore, it has been reported that oral administration of aspirin (10 mg/kg) inhibited thromboxane (TX) production by rat platelets but 20 times this dose of salicylate had no effect (5). These findings led to speculation that the antiinflammatory activity of these drugs was not related to inhibition of prostaglandin (PG) synthesis (5, 6).We have now (i) measured the concentrations of aspirin and salicylate in plasma and inflam...

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“…Serum TXB 2 is predominantly derived from platelets, with leukocytes being another source (Higgs et al 1983;Wallace and Ma 2001). In response to endogenous thrombin formation, i.e., clot formation, platelet COX-1 is maximally stimulated to produce TXA 2 , which is the major arachidonic acid metabolite produced by platelets, via COX-1, and one of the most potent platelet aggregating agent and vasoconstrictive substances known (Gilmer et al 2003;Kamath et al 2001;Smith 1989;Wallace and Ma 2001).…”

mentioning

confidence: 99%

Serum thromboxane B2 (TXB2) Determination is Influenced by Sample Incubation Temperature in Healthy Beagle Dogs

et al. 2009

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The measurement of serum thromboxane B 2 (TXB 2 ) production by platelets is a specific test for assessment of platelet cyclooxygenase (COX-1) activity following administration of non-steroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to investigate the influence of sample incubation at 37 C for one hour on serum TXB 2 concentration in comparison with incubation at room temperature. A total of 54 blood samples for serum TXB 2 measurements were collected from six healthy beagle dogs into two separate serum tubes. While one group of tubes was incubated in a 37 C water bath, the second group of tubes was left to coagulate at room temperature, both for one hour. Serum TXB 2 concentrations were measured by ELISA. The mean concentration (± SD) of serum TXB 2 in the group of samples that were incubated at 37 C was significantly (P  0.0001) higher compared to the group of samples incubated at room temperature, 1098 ± 346 g/l and 550 ± 257 g/l, respectively.The results of the study provide the information on serum TXB 2 concentration in healthy beagle dogs and demonstrate that validated methods for assessment of COX-1 activity by measurement of serum TXB 2 should be used in order to make results more reliable and comparable between different studies. The results of this study might be of great help in planning NSAID studies in dogs by providing the information that TXB 2 generation by platelets is influenced profoundly by incubation temperature.

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The source of thromboxane and prostaglandins in experimental inflammation

Cited by 115 publications

References 20 publications

Differential Regulation of Prostaglandin E2 and Thromboxane A2 Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors

Differential Regulation of Prostaglandin E2 and Thromboxane A2 Production in Human Monocytes: Implications for the Use of Cyclooxygenase Inhibitors

Pharmacokinetics of aspirin and salicylate in relation to inhibition of arachidonate cyclooxygenase and antiinflammatory activity.

Serum thromboxane B2 (TXB2) Determination is Influenced by Sample Incubation Temperature in Healthy Beagle Dogs

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