Inhibition of tissue damage by the arachidonate lipoxygenase inhibitor BW755C.

Abstract

The effects of three anti-inflammatory drugs, which interfere with arachidonic acid transformation by three different enzymes, have been compared by using a simple model of tissue damage and foreign body rejection. In groups of control rats, subcutaneously implanted polyester sponges were rejected after a mean of 12 days. Indomethacin, which selectively inhibits prostaglandin synthesis, did not significantly change time to rejection but BW755C (3-amino-1-[m-(trifluoromethyl)phenylJ-2-pyrazoline), which is a dual inhibitor of prostaglandin and leukotriene synthesis, prolonged time to rejection to a mean of 22 days. The anti-inflammatory steroid dexamethasone, which reduces arachidonic acid metabolism by stimulating the formation of a phospholipase inhibitor, prolonged time to sponge rejection as BW755C did. Treatment with BW755C or dexamethasone was also accompanied by a reduction in total leukocyte numbers in inflammatory exudates collected at 1-14 days, whereas indomethacin increased leukocyte migration on days 1 and 2 and had no effect at later times. These results suggest that the inhibition of the leukotriene-forming lipoxygenase suppresses leukocyte activation and that this leads to a reduced rate of tissue damage in experimental inflammation.The inhibition of prostaglandin synthesis accounts for the anti-inflammatory and analgesic properties of aspirin-like drugs (1). These drugs are much less effective in reducing the accumulation of inflammatory leukocytes (2), and this may explain why they do not alter the course of chronic arthritis or prevent tissue damage and incapacitation (3).The pathogenesis of chronic inflammatory conditions is closely associated with accumulation of phagocytic leukocytes. The appearance of first polymorphonuclear leukocytes (PMNs) and then mononuclear leukocytes in injured tissues is characteristic of the chronic inflammatory response. Release of lysosomal enzymes from these cells, after specific stimuli or cell death, contributes to tissue damage and necrosis (4). A putative mediator of leukocyte activation is leukotriene B4, which is a potent stimulator of chemotaxis and degranulation (5, 6) and has been detected in experimental inflammation (7) and human joint disease (8, 9).In common with the prostaglandins, leukotrienes are products of arachidonic acid peroxidation (10). The cyclo-oxygenase that catalyzes prostaglandin formation is selectively inhibited by aspirin-like drugs, but the lipoxygenase that initiates leukotriene synthesis is resistant to these drugs (11). The experimental compound BW755C (3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline) (12) is a dual cyclo-oxygenase and lipoxygenase inhibitor that prevents prostaglandin and leukotriene synthesis in vitro (13) and in vivo (14).Anti-inflammatory steroids do not inhibit either of these enzymes, but by stimulating the production of a phospholipase inhibitor (15, 16) they reduce the availability of arachidonic acid for conversion to both prostaglandins and leukotrienes. This suppression of leukotriene as w...

Relationship between arachidonic acid metabolism, myeloperoxidase activity and leukocyte infiltration in a rat model of inflammatory bowel disease

“…The subsequent increase in MPO activity in the TNB model may represent a later mononuclear cell infiltration, more characteristic of chronic inflammation. Similar changes in cellular infiltration have been described in the carrageenin sponge model of inflammation in the rat [19]. Following subcutaneous implantation of a sterile polyester sponge, there was an initial infiltration of polymorphonuclear leukocytes which, after reaching a maximum after 2 days, levelled off or began to fall.…”

Licofelone-A Novel Analgesic and Anti-Inflammatory Agent

“…These compounds effectively prolonged the time of rejection of implanted polyester sponges in rats to day 22 compared with day 12 in naïve animals. Classical NSAID indomethacin did not change the rejection time [34].…”

Novel Applications of NSAIDs: Insight and Future Perspectives in Cardiovascular, Neurodegenerative, Diabetes and Cancer Disease Therapy

“…Despite Sir Vane’s prostaglandin hypothesis has been generally accepted, various in vitro studies have suggested that additional mechanisms may have a role in the effects of NSAIDs [ 10 ]. There have been many hypothesis and studies to link the anti-inflammatory action of so-called “anti-defensive or aspirin like” [ 11 ] medicines to their ability to inhibit the activity of endogenous substances like kinines [ 11 , 12 ] slow-reacting substance in anaphylaxis (SRS-A) [ 13 ] adenosine triphosphate (ATP) [ 14 , 15 , 16 ] arachidonic acid (AA) and prostaglandin F2α (PGF2α) [ 17 , 18 ]. In the 1990s an important discovery was made from molecular and cellular studies that there are two cyclooxygenase (COX) enzymes controlling the production of prostaglandins (PGs) and thromboxane A2 (TxA 2 ).…”