Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44.
Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44.
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DOI：
10.1084/jem.20102510
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发表时间：
2011-07-04
期刊：
影响因子：
--
通讯作者：
Noble PW
中科院分区：
文献类型：
--
作者：
Li Y;Jiang D;Liang J;Meltzer EB;Gray A;Miura R;Wogensen L;Yamaguchi Y;Noble PW
Hybryonanesynthase 2和CD44是博来霉素引起的严重肺纤维化所必需的。组织纤维化是发病的主要原因，特发性肺纤维化（IPF）是一种以肺中持续基质沉积为特征的终末期疾病。控制进行性纤维化的机制尚不清楚。肌成纤维细胞在组织重塑部位积聚，并产生细胞外基质成分，如胶原蛋白和透明质酸（HA），最终损害器官功能。我们发现，肌成纤维细胞HAS2（HA合成酶2）的靶向过表达产生了一种侵袭性表型，导致博莱霉素诱导的损伤后严重的肺纤维化和死亡。从过度表达HAS2的转基因小鼠中分离的成纤维细胞表现出更大的侵袭基质的能力。间充质细胞中HAS2的条件性缺失废除了侵袭性成纤维细胞表型，阻碍了肌成纤维细胞的积累，并抑制了肺纤维化的发展。在不存在CD44的情况下，侵袭性表型和进行性纤维化都受到抑制。用CD44阻断抗体治疗可减少小鼠体内肺纤维化。最后，从IPF患者分离的成纤维细胞表现出也依赖于HAS 2和CD 44的侵袭性表型。了解导致侵袭性成纤维细胞表型的机制可能会导致治疗以严重组织纤维化为特征的疾病的新方法。
Hyaluronan synthase 2 and CD44 are required for severe lung fibrosis in response to bleomycin. Tissue fibrosis is a major cause of morbidity, and idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting matrix deposition in the lung. The mechanisms that control progressive fibrosis are unknown. Myofibroblasts accumulate at sites of tissue remodeling and produce extracellular matrix components such as collagen and hyaluronan (HA) that ultimately compromise organ function. We found that targeted overexpression of HAS2 (HA synthase 2) by myofibroblasts produced an aggressive phenotype leading to severe lung fibrosis and death after bleomycin-induced injury. Fibroblasts isolated from transgenic mice overexpressing HAS2 showed a greater capacity to invade matrix. Conditional deletion of HAS2 in mesenchymal cells abrogated the invasive fibroblast phenotype, impeded myofibroblast accumulation, and inhibited the development of lung fibrosis. Both the invasive phenotype and the progressive fibrosis were inhibited in the absence of CD44. Treatment with a blocking antibody to CD44 reduced lung fibrosis in mice in vivo. Finally, fibroblasts isolated from patients with IPF exhibited an invasive phenotype that was also dependent on HAS2 and CD44. Understanding the mechanisms leading to an invasive fibroblast phenotype could lead to novel approaches to the treatment of disorders characterized by severe tissue fibrosis.
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