TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis.
TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis.
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DOI：
10.1126/scitranslmed.3001510
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发表时间：
2010-11-10
影响因子：
17.1
通讯作者：
Hogaboam CM
中科院分区：
文献类型：
--
作者：
Trujillo G;Meneghin A;Flaherty KR;Sholl LM;Myers JL;Kazerooni EA;Gross BH;Oak SR;Coelho AL;Evanoff H;Day E;Toews GB;Joshi AD;Schaller MA;Waters B;Jarai G;Westwick J;Kunkel SL;Martinez FJ;Hogaboam CM
特发性肺纤维化是一种进行性疾病，具有高度异质性的疾病进展。特发性肺纤维化是最常见的特发性间质性肺炎，其特征是弥漫性肺泡损伤和严重纤维化引起肺功能和气体交换的持续恶化。我们检查了特发性肺纤维化患者的临床特征，在随访的第一年将其分为快速或缓慢进展。为了研究快速进展的机制，我们确定了两组之间的差异。我们实验室之前的工作已经证明toll样受体9（一种病原体识别受体）促进特发性肺纤维化患者活检培养的肺成纤维细胞的肌成纤维细胞分化。因此，我们假设TLR9在快速进展的特发性肺纤维化中既是致病分子的传感器，也是促纤维化信号。在快速进展患者的外科肺活检中，TLR9的浓度高于正常对照组织。来自快速进展患者的成纤维细胞对TLR9激动剂CpG的反应比来自对照患者的成纤维细胞更敏感。我们使用了人源SCID小鼠，并证明了接受快速进展的人肺成纤维细胞的小鼠肺纤维化比接受正常成纤维细胞的小鼠肺纤维化增加。鼻内CpG刺激加重了这种纤维化。此外，CpG还能诱导A549肺上皮细胞向纤维细胞分化和上皮向间质转化。这些数据表明，TLR9可能驱动快速进展的特发性肺纤维化的发病机制，并且是该疾病亚群的潜在指标。
Idiopathic pulmonary fibrosis is a generally progressive disorder with highly heterogeneous disease progression. The most common of the idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis is characterized by a steady worsening of lung function and gas exchange cause by diffuse alveolar damage and severe fibrosis. We examined clinical features of patients with idiopathic pulmonary fibrosis to classify them as exhibiting rapid or slowly progressive over the first year of follow-up. We identified differences between the two groups in order to investigate the mechanism of rapid progression. Previous work from our laboratory has demonstrated that Toll-like receptor 9, a pathogen recognition receptor, promotes myofibroblast differentiation in lung fibroblasts cultured from biopsies of patients with idiopathic pulmonary fibrosis. Therefore, we hypothesized that TLR9 functions as both a sensor of pathogenic molecules and a profibrotic signal in rapidly progressive idiopathic pulmonary fibrosis. TLR9 was present at higher concentrations in surgical lung biopsies from rapidly progressive patients than in tissue from normal controls. Fibroblasts from rapid progressors were more responsive to the TLR9 agonist, CpG, than were fibroblasts from control patients. We used a humanized SCID mouse and demonstrated that there was increased fibrosis in murine lungs receiving human lung fibroblasts from rapid progressors than in mice receiving normal fibroblasts. This fibrosis was exacerbated by intranasal CpG challenges. Furthermore, CpG induced the differentiation of blood monocytes into fibrocytes and the epithelial-to-mesenchymal transition of A549 lung epithelial cells. These data suggest that TLR9 may drive the pathogenesis of rapidly progressive idiopathic pulmonary fibrosis and is a potential indicator of this subset of the disease.
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DOI：
10.7326/0003-4819-142-12_part_1-200506210-00005
发表时间：
2005-06-21
影响因子：
39.2
作者：
Martinez, FJ;Safrin, S;Brown, KK
通讯作者：
Brown, KK
DOI：
10.1016/j.bbrc.2006.11.149
发表时间：
2007-02-02
影响因子：
3.1
作者：
Mehrad, Borna;Burdick, Marie D.;Strieter, Robert M.
通讯作者：
Strieter, Robert M.
DOI：
10.1152/ajprenal.00326.2007
发表时间：
2008-05-01
影响因子：
4.2
作者：
Ivanova, Larissa;Butt, Michael J.;Matsell, Douglas G.
通讯作者：
Matsell, Douglas G.
影响因子：
4.8
作者：
Hong, Kurt M.;Belperio, John A.;Strieter, Robert M.
通讯作者：
Strieter, Robert M.
DOI：
10.1164/rccm.200708-1184oc
发表时间：
2008-04-01
影响因子：
24.7
作者：
McMillan, Tracy R.;Moore, Bethany B.;Toewsl, Galen B.
通讯作者：
Toewsl, Galen B.