Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis
Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis
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DOI：
10.1164/rccm.200603-333oc
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发表时间：
2006-08-15
影响因子：
24.7
通讯作者：
Vogel, Wolfgang F.
中科院分区：
文献类型：
--
作者：
Avivi-Green, Carmel;Singal, Mayank;Vogel, Wolfgang F.
原理：Discoidin 结构域受体 1 (DDR1) 是一种由天然胶原蛋白激活的酪氨酸激酶。基于先前的研究结果显示特发性肺纤维化患者的支气管肺泡灌洗细胞中 DDR1 表达增加，我们假设 DDR1 介导肺损伤后的疾病进展。目的：研究 DDR1 敲除和野生型小鼠对博来霉素诱导的肺损伤的炎症和纤维化反应。方法：年龄和性别匹配的 DDR1 敲除和野生型 C57BL/6 小鼠接受单次注射气管内分别滴注2 U/kg博莱霉素或生理盐水。 2周后，使用免疫组织化学、实时聚合酶链反应、TUNEL测定、ELISA、荧光激活细胞分选和蛋白质印迹分析来评估肺部炎症和纤维化。测量和主要结果：与野生型动物相比，DDR1缺失小鼠在很大程度上免受博来霉素诱导的损伤。博来霉素诱导的胶原蛋白水平和生腱蛋白-C mRNA 水平的增加在基因敲除动物中被消除。此外，与野生型动物相比，这些动物的肌成纤维细胞扩增和细胞凋亡要低得多。通过灌洗细胞计数和细胞因子 ELISA 证实基因敲除小鼠不存在炎症。对受损肺组织的蛋白质印迹分析显示，DDR1 缺失小鼠无法通过 p38 MAPK 激活来响应博莱霉素损伤，这在野生型小鼠中很容易观察到。结论：DDR1 表达是肺部炎症和纤维化发生的先决条件。因此，阻断 DDR1 可能是肺纤维化患者的一种新型治疗干预措施。
Rationale: Discoidin domain receptor 1 (DDR1) is a tyrosine kinase activated by native collagens. Based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 mediates disease progression after lung injury.Objectives: To investigate the inflammatory and fibrotic responses of DDR1 knockout and wild-type mice to bleomycin-induced lung injury.Methods: Age- and sex-matched DDR1 knockout and wild-type C57BL/6 mice received a single intratracheal instillation of 2 U/kg bleomycin or saline, respectively. After 2 wk, lung inflammation and fibrosis were assessed using immunohistochemistry, real-time polymerase chain reaction, TUNEL assay, ELISA, fluorescence-activated cell sorting, and Western blot analysis.Measurements and Main Results: Compared with wild-type animals, DDR1-null mice were largely protected against bleomycin-induced injury. Bleomycin-induced increases in Collagen protein levels and tenascin-C mRNA levels were abrogated in knockout animals. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and a cytokine ELISA. Western blot analysis of injured lung tissue revealed that DDR1-null mice failed to respond to the bleomycin insult with p38 MAPK activation, which was readily observed in wild-type mice.Conclusions: DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis. Blockade of DDR1 may therefore be a novel therapeutic intervention in patients with pulmonary fibrosis.