The role of heparanase in pulmonary cell recruitment in response to an allergic but not non-allergic stimulus.
The role of heparanase in pulmonary cell recruitment in response to an allergic but not non-allergic stimulus.
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DOI：
10.1371/journal.pone.0127032
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Spina D
中科院分区：
文献类型：
--
作者：
Morris A;Wang B;Waern I;Venkatasamy R;Page C;Schmidt EP;Wernersson S;Li JP;Spina D
乙酰肝素酶是一种内切-β-葡萄糖醛酸酶，其特异性切割细胞外基质中的硫酸乙酰肝素蛋白聚糖。这种酶的表达在包括炎症在内的几种病理条件下增加。我们研究了乙酰肝素酶在过敏性和非过敏性肺细胞募集的背景下，使用乙酰肝素酶敲除（Hpa-/-）小鼠作为模型的肺部炎症的作用。在局部递送LPS或酵母聚糖后，在Hpa-/-和野生型（WT）对照之间没有发现中性粒细胞向肺的募集的显著差异。类似地，在用乙酰肝素酶抑制剂处理的WT小鼠中，中性粒细胞募集未被抑制。然而，在过敏性炎症模型中，Hpa-/-小鼠显示出显著减少的嗜酸性粒细胞（但不是嗜中性粒细胞）向气道的募集，这也与变应原诱导的支气管高反应性降低有关，表明乙酰肝素酶表达与过敏反应有关。这通过在WT过敏小鼠中使用乙酰肝素酶抑制剂的药理学治疗进一步证明。对不同严重程度的慢性阻塞性肺疾病（COPD）患者的肺标本进行检查发现乙酰肝素酶表达增加。因此，已经确定乙酰肝素酶有助于变应原诱导的嗜酸性粒细胞募集到肺中，并且可以为开发用于治疗哮喘和其它变应性疾病的抗炎药物提供新的治疗靶点。
Heparanase is an endo-β-glucuronidase that specifically cleaves heparan sulfate proteoglycans in the extracellular matrix. Expression of this enzyme is increased in several pathological conditions including inflammation. We have investigated the role of heparanase in pulmonary inflammation in the context of allergic and non-allergic pulmonary cell recruitment using heparanase knockout (Hpa-/-) mice as a model. Following local delivery of LPS or zymosan, no significant difference was found in the recruitment of neutrophils to the lung between Hpa-/- and wild type (WT) control. Similarly neutrophil recruitment was not inhibited in WT mice treated with a heparanase inhibitor. However, in allergic inflammatory models, Hpa-/- mice displayed a significantly reduced eosinophil (but not neutrophil) recruitment to the airways and this was also associated with a reduction in allergen-induced bronchial hyperresponsiveness, indicating that heparanase expression is associated with allergic reactions. This was further demonstrated by pharmacological treatment with a heparanase inhibitor in the WT allergic mice. Examination of lung specimens from patients with different severity of chronic obstructive pulmonary disease (COPD) found increased heparanase expression. Thus, it is established that heparanase contributes to allergen-induced eosinophil recruitment to the lung and could provide a novel therapeutic target for the development of anti-inflammatory drugs for the treatment of asthma and other allergic diseases.
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