Distribution of cyclooxygenase isoforms in murine chronic granulomatous inflammation. Implications for future anti-inflammatory therapy.
Inhibition of the enzyme cyclooxygenase (COX) is the basis for the mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). COX exists as a constitutive (COX-1) and a mitogen-inducible (COX-2) isoform. The relative contribution of COX-1 and COX-2 to inflammation is unknown. This study investigated COX activity and the distribution of COX-1 and COX-2 during the development of a murine air pouch model of chronic granulomatous inflammation. COX activity progressively rose and was maximal at day 14. Of the COX metabolites measured, PGE2 was the greatest > 6-keto PGF1a > TXB2 > PGF2a. By day 7, COX-2-labelled fibroblast- and macrophage-like cells were observed and their number and distribution increased with time. At all time points, endothelial cells of venules in the loose connective tissue of the dermis showed immunoreactivity for COX-2. After day 14, labelling of capillaries in the granuloma was also observed. This study is the first to show that COX-2 is the predominant COX isoform in all stages of the inflammatory response. These results suggest that selective inhibition of COX-2 may prove more beneficial, with fewer gastric and renal side-effects, than existing NSAID therapy for the treatment of chronic inflammatory diseases.
Appleton
I
I
Department of Experimental Pathology, William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, U.K.
Tomlinson
A
A
Mitchell
J A
JA
Willoughby
D A
DA
D000818:Animals; D002908:Chronic Disease; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006099:Granuloma / Q000201:enzymology* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*
D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases