Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation (Retracted Article. See vol 181, pg 6671, 2008)
Suppression of discoidin domain receptor 1 by RNA interference attenuates lung inflammation (Retracted Article. See vol 181, pg 6671, 2008)
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DOI：
10.4049/jimmunol.176.3.1928
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Arimura, K
中科院分区：
文献类型：
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作者：
Matsuyama, W;Watanabe, M;Arimura, K
盘状蛋白结构域受体1 （DDR1）是一种酪氨酸激酶受体，其配体为胶原。最近，我们报道了DDR1在体外和特发性肺纤维化中与人白细胞细胞因子产生和体内表达的关联。然而，其在体内炎症中的作用尚未完全阐明。小干扰RNA （Small interference RNA, siRNA）可以诱导特异性抑制体外和体内基因的表达。在这项研究中，使用博莱霉素诱导的肺纤维化小鼠模型，我们经鼻给药siRNA抗DDR1，并评估肺组织变化、细胞因子表达和信号分子激活。组织学上，抗DDR1的siRNA成功地降低了体内DDR1的表达，并减弱了博莱霉素诱导的炎症细胞浸润。此外，它显著降低了支气管肺泡灌洗液中炎症细胞计数和细胞因子如MCP-1、MIP-1 α和MIP-2的浓度。随后，博莱霉素诱导的支气管肺泡灌洗液tgf - β上调被显著抑制，肺内胶原沉积减少。此外，抗DDR1的siRNA显著抑制了博莱霉素诱导的肺部P38 MAPK激活。综上所述，我们认为DDR1参与了博莱霉素诱导的肺部炎症和纤维化的发展。
Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase whose ligand is collagen. Recently, we have reported the association of DDR1 in the cytokine production of human leukocytes in in vitro and in vivo expression in idiopathic pulmonary fibrosis. However, its role in in vivo inflammation has not been fully elucidated. Small interference RNA (siRNA) can induce specific suppression of in vitro and in vivo gene expression. In this study, using a bleomycin-induced pulmonary fibrosis mouse model, we administered siRNA against DDR1 transnasally and evaluated histological changes, cytokine expression, and signaling molecule activation in the lungs. Histologically, siRNA against DDR1 successfully reduced in vivo DDR1 expression and attenuated bleomycin-induced infiltration of inflammatory cells. Furthermore, it significantly reduced inflammatory cell counts and concentrations of cytokines such as MCP-1, MIP-1 alpha, and MIP-2 in bronchoalveolar lavage fluid. Subsequently, bleomycin-induced up-regulation of TGF-beta in bronchoalveolar lavage fluid was significantly inhibited, and collagen deposition in the lungs was reduced. Furthermore, siRNA against DDR1 significantly inhibited bleomycin-induced P38 MAPK activation in the lungs. Considered together, we propose that DDR1 contributes to the development of bleomycin-induced pulmonary inflammation and fibrosis.