The role of the receptor for advanced glycation end-products in lung fibrosis
The role of the receptor for advanced glycation end-products in lung fibrosis
复制标题
DOI：
10.1152/ajplung.00075.2007
复制
发表时间：
2007-12-01
影响因子：
4.9
通讯作者：
Yamaya, Mutsuo
中科院分区：
文献类型：
--
作者：
He, Mei;Kubo, Hiroshi;Yamaya, Mutsuo
肺纤维化的发病机制尚不清楚。晚期糖基化终产物受体（receptor for advanced glycation end-products，简称AGEs）是一种多配体受体，已知参与多种器官的纤维化变化过程，如腹膜纤维化和肾纤维化。本研究的目的是检查肺内滴注博莱霉素诱导的小鼠肺损伤的急性炎症和慢性纤维化阶段中的肺纤维化的贡献。在野生型和RAGE缺陷（RAGE-/-）小鼠中评价博来霉素诱导的肺纤维化。博莱霉素给药野生型小鼠引起最初的肺炎，演变成纤维化。虽然BLM-/-小鼠产生了类似的早期炎症反应，但这些小鼠在很大程度上免受博来霉素的晚期纤维化影响。由RAGE缺乏提供的保护伴随着有效的RAGE诱导的促纤维化细胞因子转化生长因子（TGF）-β和PDGF的肺水平降低。此外，博莱霉素给药诱导高迁移率族蛋白1（HMGB- 1）的生产，其中一个配体的ESTA，从炎症细胞积累的空气空间。与HMGB- 1共培养诱导野生型小鼠肺泡II型上皮细胞的上皮-间质转化（EMT）。然而，肺泡II型上皮细胞来源于EMT-/-小鼠没有响应HMGB- 1治疗，这样的EMT/ HMGB-1轴可能发挥重要作用。此外，博来霉素给药仅在野生型小鼠肺中诱导促纤维化细胞因子TGF-β和PDGF。我们的研究结果表明，EMT和促纤维化细胞因子的产生有助于博莱霉素诱导的肺纤维化。因此，肺纤维化可能是一个新的治疗靶点。
The pathogenesis of pulmonary fibrosis remains unclear. The receptor for advanced glycation end-products ( RAGE) is a multi-ligand receptor known to be involved in the process of fibrotic change in several organs, such as peritoneal fibrosis and kidney fibrosis. The aim of this study was to examine the contribution of RAGE during the acute inflammation and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Bleomycin-induced lung fibrosis was evaluated in wild-type and RAGE-deficient ( RAGE-/-) mice. Bleomycin administration to wild-type mice caused an initial pneumonitis that evolved into fibrosis. While RAGE -/- mice developed a similar early inflammatory response, the mice were largely protected from the late fibrotic effects of bleomycin. The protection afforded by RAGE deficiency was accompanied by reduced pulmonary levels of the potent RAGE-inducible profibrotic cytokines transforming growth factor (TGF)-beta and PDGF. In addition, bleomycin administration induced high mobility group box 1 ( HMGB- 1) production, one of the ligands of RAGE, from inflammatory cells that accumulated within the air space. Coculture with HMGB- 1 induced epithelial-mesenchymal transition ( EMT) in alveolar type II epithelial cells from wild-type mice. However, alveolar type II epithelial cells derived from RAGE -/- mice did not respond to HMGB- 1 treatment, such that the RAGE/ HMGB-1 axis may play an important role in EMT. Also, bleomycin administration induced profibrotic cytokines TGF-beta and PDGF only in wild-type mouse lungs. Our results suggested that RAGE contributes to bleomycin-induced lung fibrosis through EMT and profibrotic cytokine production. Thus, RAGE may be a new therapeutic target for pulmonary fibrosis.