Roxithromycin attenuates inflammation via modulation of RAGE-influenced calprotectin expression in a neutrophilic asthma model

BACKGROUND: Roxithromycin (RXM), a macrolide antibiotic, exhibits anti-asthmatic effects, but its specific mechanism of action remains elusive. We evaluated the effects of RXM on airway inflammation, the expression of calprotectin, and the activity of the receptor of advanced glycation end products (RAGE) to determine whether RXM alleviates inflammation by regulating RAGE activation, and thereby calprotectin expression, in neutrophilic asthma. METHODS: Male Brown Norway rats were sensitized with ovalbumin (OVA) and Freund’s complete adjuvant (FCA) mixture, followed by OVA challenge to induce neutrophilic asthma. RXM (30 mg/kg) or FPS-ZM1 (RAGE inhibitor, 1.5 mg/kg) was administered 30 min prior to each challenge. The infiltration of airway inflammatory cells and cytokines, as well as the expression of calprotectin and RAGE, was assessed. RESULTS: The expression of airway inflammatory cells and cytokines was found to be significantly elevated in OVA + FCA-induced rats. Increased expression of both calprotectin and RAGE was also detected in OVA + FCA-induced asthma [bronchoalveolar lavage fluid (BALF) calprotectin: 15.07±1.79 vs. 3.86±0.69 ng/mL; serum calprotectin: 20.47±1.64 vs. 9.29±1.31 ng/mL; lung tissue homogenates calprotectin: 28.82±1.01 vs. 12.02±1.38 ng/mg; BALF RAGE: 762.93±36.47 vs. 294.25±45.92 ng/mL; serum RAGE: 906.43±58.95 vs. 505.60±30.16 ng/mL; lung tissue homogenates RAGE: 1,585.24±177.59 vs. 461.53±63.40 ng/mg; all P<0.001]. However, all of these changes were interrupted by RXM and FPS-ZM1. CONCLUSIONS: RXM exerted similar effects as the RAGE inhibitor FPS-ZM1 in terms of reducing airway inflammation and downregulating the expression of calprotectin and RAGE in a neutrophilic asthma model. Our findings provide novel insights into the mechanisms underlying the effect of RXM pretreatment on neutrophilic asthma. Furthermore, FPS-ZM1 may be useful as an intervention specific to the neutrophilic asthma phenotype.