The role of high mobility group box1 in pulmonary fibrosis
The role of high mobility group box1 in pulmonary fibrosis
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DOI：
10.1165/rcmb.2007-0330oc
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发表时间：
2008-10-01
影响因子：
6.4
通讯作者：
Nakanishi, Yoichi
中科院分区：
文献类型：
--
作者：
Hamada, Naoki;Maeyama, Takashige;Nakanishi, Yoichi
高迁移率族蛋白1（HMGB1）最初是作为核结合蛋白被发现的，并且已知在急性肺损伤中起重要作用。然而，HMGB1在肺纤维化中的作用尚未得到解决。因此，我们用酶联免疫吸附法测定了特发性肺纤维化（IPF）、非特异性间质性肺炎、胶原血管病相关性间质性肺炎和过敏性肺炎（HP）患者血清和支气管肺泡灌洗液（BALF）中的HMGB1水平。我们还评估了博莱霉素诱导的小鼠肺纤维化中HMGB1的表达，并检查了抗HMGB1抗体和丙酮酸乙酯的作用，其抑制肺泡巨噬细胞分泌HMGB1。此外，我们还研究了HMGB1对体外成纤维细胞增殖、凋亡和胶原合成的影响。与对照组相比，间质性肺病患者血清HMGB1水平无显著升高。与对照组相比，IPF和HP患者BALF HMGB1水平显著升高。HMGB 1蛋白主要在IPF的炎症细胞和增生的上皮细胞中检测到。在博莱霉素诱导的小鼠肺纤维化中，HMGB1蛋白在早期主要在细支气管上皮细胞中上调，在后期纤维化病变中主要在肺泡上皮细胞和炎性细胞中上调。腹腔内注射抗HMGB1抗体或丙酮酸乙酯可显著减轻该模型中的肺部炎症和纤维化。HMGB1显著诱导培养的成纤维细胞增殖，但不诱导细胞凋亡或胶原合成。HMGB1有可能成为抗肺纤维化和急性肺损伤的一个有希望的靶点。
High mobility group box1 protein (HMGB1) was originally discovered as a nuclear binding protein, and is known to play an important role in acute lung injury. However, the role of HMGB1 in pulmonary fibrosis has not been addressed. Therefore, we measured the HMGB1 levels in serum and bronchoalveolar lavage fluids (BALF) from patients with idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, interstitial pneumonia associated with collagen vascular diseases, and hypersensitivity pneumonitis (HP) by enzyme-linked immunosorbent assay. We also assessed the HMGB1 expression in bleomycin-induced pulmonary fibrosis in mice, and examined the effect of anti-HMGB1 antibody and ethyl pyluvate, which inhibits the HMGB1 secretion from alveolar macrophages. In addition, we examined the effect of HMGB1 on fibroblast proliferation, apoptosis, and Collagen synthesis in vitro. Serum HMGB1 levels were not significantly increased in interstitial lung diseases compared with control subjects. BALF HMGB1 levels were significantly increased in IPF and HP compared with control subjects. HMGB1 protein was predominantly detected in inflammatory cells and hyperplasic epithelial cells in IPF. In bleomycin-induced pulmonary fibrosis in mice, HMGB1 protein was predominantly up-regulated in bronchiolar epithelial cells at early phase and in alveolar epithelial and inflammatory cells in fibrotic lesions at later phase. Intraperitoneal injection of anti-HMGB1 antibody or ethyl pyluvate significantly attenuated lung inflammation and fibrosis in this model. HMGB1 significantly induced proliferation, but not apoptosis or Collagen synthesis on cultured fibroblasts. HMGB1 may be a promising target against pulmonary fibrosis as well as acute lung injury.