Anti-inflammatory activity of macrolide antibiotics

The effect of four macrolide antibiotics (roxithromycin, clarithromycin, er ythromycin, and azithromycin) on the generation of some mediators and cytok ines involved in the inflammatory process has been studied both in vivo and in vitro. Rat carrageenin pleurisy was used as a model of acute inflammati on, and the macrolides were administered (10, 20, and 40 mg/kg p.o.) 1 h be fore the carrageenin challenge. Exudate volume and leukocyte accumulation w ere both dose-dependently reduced by roxithromycin, clarithromycin and eryt hromycin in either normal or adrenalectomized animals. Furthermore, in norm al rats, prostaglandin (PG) E-2, nitrate plus nitrite, and tumor necrosis f actor-alpha levels in pleural exudate were significantly reduced by these m acrolides. Roxithromycin appeared more effective than erythromycin and clar ithromycin, whereas azithromycin only slightly affected the inflammatory re action. None of the macrolides were able to modify leukotriene B-4 exudate levels. In vitro experiments have shown that the four macrolides (5-80 mu M ) reduced in a concentration-dependent manner the production of 6-keto-PGF( 1 alpha), NO2-, tumor necrosis factor-alpha, interleukin-1 beta, and interl eukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, t he inhibition of 6-keto-PGF(1 alpha) and NO2- production by roxithromycin a nd erythromycin was not dependent on direct inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activity because it appears to be relat ed to the inhibition of cyclooxygenase-2 and inducible nitric oxide synthas e protein expression. In conclusion, the present study shows that macrolide antibiotics have anti-inflammatory activity, which likely depends on their ability to prevent the production of proinflammatory mediators and cytokin es, and suggest that these agents, particularly roxithromycin, can exert th erapeutic effects independently of their antibacterial activity.