MODULATION OF POLYMORPHONUCLEAR LEUKOCYTE RESPONSIVENESS BY COPPER(II)(2) (NIFLUMATE)(4)

Antiinflammatory activities and modulations of PMNL responses produced by treatment with tetrakis-mu-2- [3-(trifluoromethyl)-phenyl] aminoni cotinatodicopper (II) [Cu(II)(2)(niflumate)(4)] and niflumic acid were studied in isologous serum-induced rat pleurisy. Doses of 10 or 30 mg /kg (35 or 106 mu mol/kg) of niflumic acid or Cu(II)(2) (niflumate)(4) (8 or 23 mu mol/kg) caused significant (p < 0.01) reductions in pleur al exudate and number of polymorphonuclear leukocytes (PMNLs) in the e xudate, While both doses of Cu(II)(2)(niflumate)(4) produced significa nt dose-related reductions in both parameters, only the higher dose of niflumic acid produced a significant dose-related reduction in both p arameters. Boyden chamber measurements of N-formyl-methionyl-leucyl-ph enylalanine (f-MLP) chemotaxis by PMNLs incubated with 10 or 30 mu g/m l niflumic acid (35 or 106 nmol/ml) or Cu(II)(2)(niflumate)(4) (8 or 2 3 nmol/ml) were significantly (p < 0.01 to p < 0.001) decreased in dos e-related fashions. Chemotaxis of PMNLs from pleuritic rats treated or ally with 10 or 30 mg/kg niflumic acid or Cu(II)(2)(niflumate)(4) was significantly (p < 0.001) inhibited by the larger dose of niflumic aci d and both doses of Cu(II)(2) (niflumate)(4). Opsonized zymosan (OZ)-s timulated chemiluminescence (CL) of PMNLs from pleuritic rats treated orally with these same doses of niflumic acid or Cu(II)(2)(niflumate)( 4) was only significantly (p < 0.05 or p < 0.01 respectively) decrease d by the larger doses. Superoxide (O-2(-)) production by these cells w as significantly decreased by the larger dose of niflumic acid (p<0.05 ) while both doses of Cu(II)(2)(niflumate)(4) produced significant (p < 0.05 to p < 0.01) decreases. Recovery of the decreased PMNL response in burned rats was also studied following treatment with these two co mpounds. Oral treatment of non-burned rats with 1 mg/kg niflumic acid (4 mu mol/kg) or Cu(II)(2)(niflumate)(4) (1 mu mol/kg) did not affect OZ-stimulated O-2(-) production while decreased O-2(-) production in n on-treated scald-burned rats was reversed by oral treatment with eithe r niflumic acid or Cu(II)(2)(niflumate)(4). It is concluded that Cu(II )(2)(niflumate)(4) is a more effective antiinflammatory agent than nif lumic acid and more effective modulation of PMNL responsiveness may ex plain its beneficial antipleuritic and burn-injury recovery effects. F ormation of the copper complex of niflumic acid in vivo may also accou nt for its beneficial antiinflammatory effects and recovery of depress ed PMNL responsiveness in burned rats.