title: Suppression of inducible nitric oxide synthase expression and nitric oxide production by macrolide antibiotics in sulfur mustard-exposed airway epithelial cells.
abstract: Sulfur mustard, a vesicant chemical warfare agent, causes airway injury due to massive release of destructive enzymes and mediators of inflammation. Nitric oxide plays an important yet controversial role in inflammation. An impressive number of reports suggest that excessive amount of nitric oxide may promote inflammation-induced cell injury and death. Overproduction of nitric oxide is catalysed by up-regulated expression of the inducible isoform of nitric oxide synthase (iNOS). In this study, we used quantum dot-mediated immunocytochemistry to analyse iNOS expression and flow cytometry to analyse the intracellular nitric oxide production in sulfur mustard-exposed normal human small airway epithelial cells and bronchial/tracheal epithelial cells and studied the effect of four US Food and Drug Administration-approved macrolide antibiotics, namely, azithromycin, clarithromycin, erythromycin and roxithromycin. Exposure to 100 microM sulfur mustard significantly up-regulated iNOS expression and resulted in overproduction of nitric oxide in these cells. Addition of macrolide antibiotics to 100 microM in the medium reduced both iNOS expression and nitric oxide production to near normal level. Thus, the current study provides in vitro evidence of the immunomodulatory effects of macrolide antibiotics in sulfur mustard-exposed airway epithelial cells. These results suggest that macrolide antibiotics may serve as potential vesicant respiratory therapeutics through mechanisms independent of their antibacterial activity.
authors.affiliation: Department of Biology, Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
authors.forename: Xiugong
authors.initials: X
authors.lastname: Gao
authors.forename: Radharaman
authors.initials: R
authors.lastname: Ray
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Prabhati
authors.initials: P
authors.lastname: Ray
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002619:Chemical Warfare Agents / Q000633:toxicity; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018942:Macrolides / Q000494:pharmacology*; D009151:Mustard Gas / Q000633:toxicity*; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002619:Chemical Warfare Agents; D018942:Macrolides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D009151:Mustard Gas