Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4
Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4
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DOI：
10.1172/jci38644
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Noble, Paul W.
中科院分区：
文献类型：
--
作者：
Jiang, Dianhua;Liang, Jiurong;Noble, Paul W.
肺纤维化是对损伤的进行性失调反应，由于过量的细胞外基质产生而最终导致肺功能受损。硫酸乙酰肝素蛋白聚糖syndecan-4在介导成纤维细胞-基质相互作用中是重要的，但其在肺纤维化中的作用尚未探讨。为了研究这个问题，我们使用博莱霉素气管内滴注作为急性肺损伤和纤维化的模型。我们发现博来霉素治疗增加了syndecan-4的表达。此外，我们观察到博来霉素治疗的syndecan-4-null（Sdc 4（-/-））小鼠中中性粒细胞募集显著减少，肌成纤维细胞募集和间质纤维化增加。随后，我们确定了CXCL 10（一种抗纤维化趋化因子）和syndecan-4之间的直接相互作用，该相互作用在纤维化过程中抑制原代肺成纤维细胞迁移; CXCL 10的肝素结合结构域（而非CXCR 3结构域）突变减弱了这种作用。类似地，来自肺纤维化患者的成纤维细胞的迁移在CXCL 10蛋白在CXCR 3结合中缺陷的存在下被抑制。此外，施用重组CXCL 10蛋白抑制WT小鼠中的纤维化，但不抑制Sdc 4（-/-）小鼠中的纤维化。总的来说，这些数据表明多配体蛋白聚糖-4和CXCL 10在肺间质隔室中的直接相互作用用于抑制成纤维细胞募集和随后的纤维化。因此，给予CXCR 3结合缺陷的CXCL 10蛋白可能代表了肺纤维化的新疗法。
Pulmonary fibrosis is a progressive, dysregulated response to injury culminating in compromised lung function due to excess extracellular matrix production. The heparan sulfate proteoglycan syndecan-4 is important in mediating fibroblast-matrix interactions, but its role in pulmonary fibrosis has not been explored. To investigate this issue, we used intratracheal instillation of bleomycin as a model of acute lung injury and fibrosis. We found that bleomycin treatment increased syndecan-4 expression. Moreover, we observed a marked decrease in neutrophil recruitment and an increase in both myofibroblast recruitment and interstitial fibrosis in bleomycin-treated syndecan-4-null (Sdc4(-/-)) mice. Subsequently, we identified a direct interaction between CXCL10, an antifibrotic chemokine, and syndecan-4 that inhibited primary lung fibroblast migration during fibrosis; mutation of the heparin-binding domain, but not the CXCR3 domain, of CXCL10 diminished this effect. Similarly, migration of fibroblasts from patients with pulmonary fibrosis was inhibited in the presence of CXCL10 protein defective in CXCR3 binding. Furthermore, administration of recombinant CXCL10 protein inhibited fibrosis in WT mice, but not in Sdc4(-/-) mice. Collectively, these data suggest that the direct interaction of syndecan-4 and CXCL10 in the lung interstitial compartment serves to inhibit fibroblast recruitment and subsequent fibrosis. Thus, administration of CXCL10 protein defective in CXCR3 binding may represent a novel therapy for pulmonary fibrosis.