Department of Otorhinolaryngology, Shiga University of Medical Science, Otsu, Japan.
Am J Rhinol Allergy. 2011 Mar-Apr;25(2):69-74. doi: 10.2500/ajra.2011.25.3562.
Heparin is one of the most important anticoagulant drugs. It has been known that heparin also possesses anti-inflammatory activities. Mucus hypersecretion is an important characteristic of airway inflammation. However, little is known about the regulatory effects of heparin on mucus hypersecretion in airway epithelial cells. To elucidate the anti-inflammatory function of heparin in airway epithelial cells, we examined the in vivo effects of heparin on mucus hypersecretion and neutrophil infiltration in rat nasal epithelium. We also examined the in vitro effects of heparin on mucin production and IL-8 secretion from cultured human airway epithelial cells.
We induced hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium by intranasal lipopolysaccharide (LPS) instillation. The effects of intranasal instillation with heparin on mucus production and neutrophil infiltration were examined. in vitro effects of heparin on airway epithelial cells were examined using cultured NCI-H292 cells. Mucus secretion was evaluated by enzyme-linked immunosorbent assay using an anti-MUC5AC monoclonal antibody.
Intranasal instillation with unfractionated heparin (UFH; 100 IU/0.1 mL) or low molecular weight heparin (LMWH; 100 IU/0.1 mL) at 30 minutes before LPS instillation significantly inhibited LPS-induced mucus production and neutrophil infiltration in rat nasal epithelium. UFH or LMWH inhibited tumor necrosis factor alpha (10 ng/mL)-induced secretion of MUC5AC and IL-8 from NCI-H292 cells in a dose-dependent manner (0.01-10 IU/mL). MUC5AC mRNA expression was also significantly inhibited.
These results indicate that heparin inhibits airway mucus hypersecretion in airway epithelial cells directly and indirectly through the suppression of IL-8 secretion and neutrophil infiltration.
肝素是最重要的抗凝药物之一。已知肝素还具有抗炎活性。黏液过度分泌是气道炎症的一个重要特征。然而，关于肝素对气道上皮细胞黏液过度分泌的调节作用知之甚少。为了阐明肝素在气道上皮细胞中的抗炎功能，我们研究了肝素对大鼠鼻上皮黏液过度分泌和中性粒细胞浸润的体内作用。我们还研究了肝素对培养的人气道上皮细胞黏蛋白产生和 IL-8 分泌的体外作用。
我们通过鼻腔内给予脂多糖（LPS）诱导大鼠鼻上皮的肥大和化生改变。通过鼻腔内给予肝素观察对黏液产生和中性粒细胞浸润的影响。使用培养的 NCI-H292 细胞研究肝素对气道上皮细胞的体外作用。使用抗 MUC5AC 单克隆抗体通过酶联免疫吸附试验评估黏液分泌。
在 LPS 给药前 30 分钟鼻腔内给予未分级肝素（UFH；100 IU/0.1 mL）或低分子量肝素（LMWH；100 IU/0.1 mL）显著抑制 LPS 诱导的大鼠鼻上皮黏液产生和中性粒细胞浸润。UFH 或 LMWH 以剂量依赖性方式（0.01-10 IU/mL）抑制肿瘤坏死因子-α（10 ng/mL）诱导的 NCI-H292 细胞黏蛋白 5AC 和 IL-8 的分泌。MUC5AC mRNA 表达也显著受到抑制。
这些结果表明肝素通过抑制 IL-8 分泌和中性粒细胞浸润直接和间接抑制气道黏液过度分泌。
