Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Gu X

PROVIDER: S-EPMC8039670 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Gu Xiaofei X Shu Danni D Ying Songmin S Dai Yuanrong Y Zhang Qi Q Chen Xinmiao X Chen Huijun H Dai Wei W

Annals of translational medicine 20210301 6

<h4>Background</h4>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.<h4>Methods</h4>Male Brown Norway rats were se ...[more]

PMID: 33850891

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Project description:Apolipoprotein A-I (apoA-I) is a key component of high-density lipoproteins that mediates reverse cholesterol transport from cells and reduces vascular inflammation. We investigated whether endogenous apoA-I modulates ovalbumin (OVA)-induced airway inflammation in mice. We found that apoA-I expression was significantly reduced in the lungs of OVA-challenged, compared with saline-challenged, wild-type (WT) mice. Next, to investigate the role of endogenous apoA-I in the pathogenesis of OVA-induced airway inflammation, WT and apoA-I(-/-) mice were sensitized by intraperitoneal injections of OVA and aluminum hydroxide, followed by multiple nasal OVA challenges for 4 weeks. OVA-challenged apoA-I(-/-) mice exhibited a phenotype of increased airway neutrophils compared with WT mice, which could be rescued by an administration of a 5A apoA-I mimetic peptide. Multiple pathways promoted neutrophilic inflammation in OVA-challenged apoA-I(-/-) mice, including the up-regulated expression of (1) proinflammatory cytokines (IL-17A and TNF-α), (2) CXC chemokines (CXCL5), (3) vascular adhesion molecules (i.e., vascular cell adhesion molecule-1), and (4) granulocyte colony-stimulating factors (G-CSF). Because concentrations of G-CSF in bronchoalveolar lavage fluid (BALF) were markedly increased in OVA-challenged apoA-I(-/-) mice, we hypothesized that enhanced G-CSF expression may represent the predominant pathway mediating increased neutrophilic inflammation. This was confirmed by the intranasal administration of a neutralizing anti-G-CSF antibody, which significantly reduced BALF neutrophilia by 72% in OVA-challenged apoA-I(-/-) mice, compared with mice that received a control antibody. We conclude that endogenous apoA-I negatively regulates OVA-induced neutrophilic airway inflammation, primarily via a G-CSF-dependent mechanism. Furthermore, these findings suggest that apoA-I may play an important role in modulating the severity of neutrophilic airway inflammation in asthma.

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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