title: Regulation of macrophage collagenase, prostaglandin, and fibroblast-activating-factor production by anti-inflammatory agents: different regulatory mechanisms for tissue injury and repair.
abstract: Activation of macrophages results in the production of tissue destructive mediators and enzymes including prostaglandins (PGE) and collagenase. In addition, activated macrophages also generate mediators which enhance connective tissue formation through their effects on fibroblast growth. To determine whether the pro-inflammatory mediators and the mediator(s) involved in tissue repair are under the same regulatory control, guinea pig macrophage cultures were treated with various pharmacologic agents and their supernatants monitored for biologic activity. The nonsteroidal anti-inflammatory agent, indomethacin, and the glucocorticoid, dexamethasone, at pharmacologic concentrations inhibited not only prostaglandin synthesis (greater than 90%) but also the production of collagenase (greater than 90%). Colchicine, a microtubule disruptive agent, but not the inactive form, lumicolchicine, markedly diminished the production of collagenase independently of prostaglandin synthesis. In contrast to the inhibitory effects of these anti-inflammatory agents on PGE and collagenase production, indomethacin did not inhibit the production of macrophage-derived fibroblast-activating factor (FAF). Furthermore, dexamethasone at pharmacologic doses did not inhibit FAF production. Colchicine not only did not inhibit FAF, but frequently enhanced the appearance of FAF In the macrophage cultures. Thus, it appears that regulation of the production of PGE and collagenase is different than the regulation of FAF synthesis and therefore the production of these mediators can be differentially modulated. Such a dissociation may provide a basis for mononuclear cell-mediated fibroblast growth and tissue repair to occur independently of the release of PGE2 and collagenase and even following anti-inflammatory drug therapy.
authors.forename: S M
authors.initials: SM
authors.lastname: Wahl
authors.forename: L M
authors.initials: LM
authors.lastname: Wahl
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone; D005346:Fibroblast Growth Factors / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology; D006168:Guinea Pigs; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects*; D003012:Microbial Collagenase / Q000096:biosynthesis; D011458:Prostaglandins E / Q000096:biosynthesis; D014945:Wound Healing
chemical_list: D000893:Anti-Inflammatory Agents; D011458:Prostaglandins E; D005346:Fibroblast Growth Factors; D003907:Dexamethasone; D000242:Cyclic AMP; D003012:Microbial Collagenase; D015232:Dinoprostone; D003078:Colchicine; D007213:Indomethacin