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      Inducible cyclooxygenase may have anti-inflammatory properties.

      Nature medicine

      pharmacology, Animals, Sulfonamides, Rats, Wistar, Rats, metabolism, drug effects, Prostaglandin-Endoperoxide Synthases, analogs & derivatives, Prostaglandin D2, Nitrobenzenes, Neutrophils, Monocytes, Membrane Proteins, Male, Isoenzymes, drug therapy, chemically induced, Inflammation, Indomethacin, Dose-Response Relationship, Drug, Dinoprostone, Cyclooxygenase Inhibitors, Cyclooxygenase 2 Inhibitors, Cyclooxygenase 2, Cyclooxygenase 1, toxicity, Carrageenan, Anti-Inflammatory Agents, Non-Steroidal

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          Abstract

          Cyclooxygenase (COX) has two isoforms. Generally, COX 1 is constitutively expressed in most tissues, where it maintains physiological processes; inducible COX 2 is considered a pro-inflammatory enzyme and a chief target for the treatment of inflammatory diseases. Here we present evidence that COX 2 may have anti-inflammatory properties. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 hours. In this model, COX 2 protein expression peaked initially at 2 hours, associated with maximal prostaglandin E2 synthesis. However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxy delta(12-14)prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again at 48 hours. The selective COX 2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxy delta(12-14)prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. Thus, COX 2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, dominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear cell-dominated phase by generating an alternative set of anti-inflammatory prostaglandins.

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          Journal
          10.1038/9550
          10371510

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