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Vol. 292, Issue 1, 156-163, January 2000
Department of Experimental Pharmacology, University of
Naples "Federico II," Naples, Italy
The effect of four macrolide antibiotics (roxithromycin,
clarithromycin, erythromycin, and azithromycin) on the generation of
some mediators and cytokines involved in the inflammatory process has
been studied both in vivo and in vitro. Rat carrageenin pleurisy was
used as a model of acute inflammation, and the macrolides were
administered (10, 20, and 40 mg/kg p.o.) 1 h before the
carrageenin challenge. Exudate volume and leukocyte accumulation were
both dose-dependently reduced by roxithromycin, clarithromycin and erythromycin in either normal or adrenalectomized animals. Furthermore, in normal rats, prostaglandin (PG)E2, nitrate plus nitrite,
and tumor necrosis factor-
levels in pleural exudate were
significantly reduced by these macrolides. Roxithromycin appeared more
effective than erythromycin and clarithromycin, whereas azithromycin
only slightly affected the inflammatory reaction. None of the
macrolides were able to modify leukotriene B4 exudate
levels. In vitro experiments have shown that the four macrolides (5-80
µM) reduced in a concentration-dependent manner the production of
6-keto-PGF1
, NO2
, tumor
necrosis factor-, interleukin-1
, and interleukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, the
inhibition of 6-keto-PGF1 and
NO2 production by roxithromycin and
erythromycin was not dependent on direct inhibition of cyclooxygenase-2
and inducible nitric oxide synthase activity because it appears to be
related to the inhibition of cyclooxygenase-2 and inducible nitric
oxide synthase 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 cytokines, and suggest that these agents,
particularly roxithromycin, can exert therapeutic effects independently
of their antibacterial activity.
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