Synergistic antiinflammatory effect of NF-kappaB inhibitors and steroidal or non steroidal antiinflammatory drugs in the pleural inflammation induced by carrageenan in mice.

Abstract

Experiments were designed to determine whether or not inhibitors of NF-Kappa B (NF-kappaB) exhibit antiinflammatory effects when assessed in carrageenan-induced pleural inflammation in the mouse. Adult mice of both sexes received pyrrolidine dithiocarbamate (PDTC) or sulfasalazine administered intraperitoneal by at several time points before intrapleural injection of carrageenan (1%) and the exudation and the total and differential cells were analysed. PDTC or sulfasalazine largely and almost completely inhibited the leukocyte infiltration and the exudation induced by intrapleural administration of carrageenan, when assessed 4 h (but not 48 h) after carrageenan injection. The combination of subliminal doses of PDTC or sulfasalazine with steroidal (dexamethasone) or non-steroidal (indomethacin, meloxicam, nabumetone, diacerein) antiinflammatory drugs, which alone had no antinflammatory action, greatly inhibited both the pleural cell infiltration and exudation induced by carrageenan. The highest inhibition of leukocyte infiltration was observed with the combination of PDTC or sulfasalazine with dexamethesone (84 and 75%, respectively). These results indicate that nuclear factor-kappaB might play an important role in the modulation of the early phase of the pleural inflammatory response induced by carrageenan in the mouse. Furthermore, our results demonstrate for the first time a marked synergistic interaction among dexamethasone--and to a lesser extent among nonsteroidal antiinflammatory drugs--and the NF-kappaB inhibitors, suggesting that this association may be of potential interest for the management of certain inflammatory processes, including asthma therapy.