地昔帕明可抑制脂多糖刺激的人支气管上皮细胞中白细胞介素-8 的分泌，并在雪貂中解决气道炎症。

Dapsone inhibits IL-8 secretion from human bronchial epithelial cells stimulated with lipopolysaccharide and resolves airway inflammation in the ferret.

机构信息

Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA.

出版信息

Chest. 2011 Oct;140(4):980-990. doi: 10.1378/chest.10-2908. Epub 2011 Mar 24.

DOI:10.1378/chest.10-2908

PMID:21436242

Abstract

BACKGROUND

IL-8 is an important activator and chemoattractant for neutrophils that is produced by normal human bronchial epithelial (NHBE) cells through mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 pathways. Dapsone, a synthetic sulfone, is widely used to treat chronic neutrophil dermatoses. We investigated the effects of dapsone on polarized IL-8 secretion from lipopolysaccharide (LPS)-stimulated NHBE cells and further evaluated its ability to decrease LPS-induced inflammation in the ferret airway.

METHODS

NHBE cells were grown at air-liquid interface (ALI) to ciliated differentiation. Baseline and endotoxin (LPS)-stimulated IL-8 secretion was measured by enzyme-linked immunosorbent assay at air and basal sides with and without dapsone. Western blotting was used to determine signaling pathways. In vivo, ferrets were exposed to intratracheal LPS over a period of 5 days. Once inflammation was established, oral or nebulized dapsone was administered for 5 days. Intraepithelial neutrophil accumulation was analyzed histologically, and mucociliary transport was measured on the excised trachea.

RESULTS

Dapsone, 1 μg/mL, did not influence unstimulated (basal) IL-8 secretion. Apical LPS stimulation induced both apical and basolateral IL-8, but basolateral LPS increased only basolateral IL-8. Dapsone inhibited polarized IL-8 secretion from ALI-conditioned cells. Dapsone also decreased LPS-induced IL-8 mRNA level. LPS led to phosphorylation of extracellular signal-regulated kinase 1/2, but not p38 MAPK or c-Jun NH(2)-terminal kinase. LPS also induced NF-κB p65 phosphorylation, an effect that was inhibited by dapsone. Both oral and aerosol dapsone decreased LPS-induced intraepithelial neutrophil accumulation, but only treatment with aerosol dapsone restored mucociliary transport to normal.

CONCLUSIONS

Dapsone, given either systemically or as an aerosol, may be useful in treating neutrophilic airway inflammation.

摘要

背景

白细胞介素-8（IL-8）是一种重要的中性粒细胞激活趋化因子，正常的人支气管上皮（NHBE）细胞通过丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB）p65 途径产生。氨苯砜，一种合成的砜，被广泛用于治疗慢性中性粒细胞皮肤病。我们研究了氨苯砜对脂多糖（LPS）刺激的 NHBE 细胞极化 IL-8 分泌的影响，并进一步评估了其降低脂多糖诱导的雪貂气道炎症的能力。

方法

NHBE 细胞在气液界面（ALI）生长以分化为纤毛细胞。用酶联免疫吸附试验（ELISA）在空气侧和基底侧测量基础和内毒素（LPS）刺激的 IL-8 分泌，并在有和没有氨苯砜的情况下进行测量。用 Western blot 法测定信号通路。在体内，雪貂通过气管内给予 LPS 5 天来建立炎症模型。一旦炎症建立，给予口服或雾化氨苯砜 5 天。通过组织学分析上皮内中性粒细胞的积累，并测量切除的气管上的黏液纤毛运输。

结果

1μg/ml 的氨苯砜不影响未刺激（基础）的 IL-8 分泌。顶侧 LPS 刺激诱导顶侧和基底侧的 IL-8，但基底侧 LPS 仅增加基底侧的 IL-8。氨苯砜抑制 ALI 条件细胞的极化 IL-8 分泌。氨苯砜还降低了 LPS 诱导的 IL-8 mRNA 水平。LPS 导致细胞外信号调节激酶 1/2 的磷酸化，但不导致 p38 MAPK 或 c-Jun NH2-末端激酶的磷酸化。LPS 还诱导 NF-κB p65 磷酸化，该作用被氨苯砜抑制。口服和雾化氨苯砜均可减少 LPS 诱导的上皮内中性粒细胞积累，但只有雾化氨苯砜治疗才能使黏液纤毛运输恢复正常。