Macrolide Antibiotics Improve Phagocytic Capacity and Reduce Inflammation In Sulfur Mustard-Exposed Monocytes

摘要

Sulfur mustard (SM) inhalation causes apoptosis and death of airway epithelial cells as well as inflammation in the airway. Efficient clearance of the cell debris by alveolar macrophages (AMs) is necessitated to reduce the inflammation. Macrolide antibiotics have been reported to have anti- inflammatory properties by modulating the production of proinflammatory cytokines and mediators, and by improving macrophage functions. The present study investigated the effects of four FDA-approved macrolide antibiotics, namely azithromycin, clarithromycin, erythromycin, and roxithromycin, on macrophage chemotactic and phagocytotic function and on inflammatory cytokines/mediators production in vitro using SM-exposed monocyte THP-1 cells. Using flow cytometry we found that chemotaxis and phagocytosis of the monocytes reduced upon exposure to 10 micrometer SM (8.1% and 17.5%, respectively) were restored by treatment with 10 micrometer of any of the four macrolides. Cytokine measurements using real-time RT-PCR and ELISA revealed that overexpression of proinflammatory cytokines following SM exposure was decreased by 50%- 70% with macrolide treatment. Similarly, immunocytochemical detection of inducible nitric oxide synthase (iNOS) showed that exaggerated expression of iNOS induced by SM exposure was totally inhibited by treatment with macrolides. Together, these data demonstrate that macrolide antibiotics were effective in improving the degenerated chemotactic and phagocytotic functions of macrophages following SM exposure, and in reducing SM-induced overproduction of proinflammatory cytokines and mediators. These effects may lead to improved clearance of apoptotic material in the airway and ultimately result in reduced airway inflammation and injury caused by SM inhalation. Our results suggest that macrolide antibiotics may serve as potential vesicant respiratory therapeutics.