Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis
Soluble endostatin is a novel inhibitor of epithelial repair in idiopathic pulmonary fibrosis
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DOI：
10.1136/thx.2008.102814
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发表时间：
2009-02-01
期刊：
影响因子：
10
通讯作者：
Thickett, D. R.
中科院分区：
文献类型：
--
作者：
Richter, A. G.;McKeown, S.;Thickett, D. R.
背景与目的：异常的血管生成和缺陷的上皮修复是特发性肺纤维化(IPF)的重要特征。内皮抑素是一种抗血管生成的多肽，对内皮细胞有已知的作用。本研究旨在建立IPF患者支气管肺泡灌洗液(BALF)中内皮抑素的水平，并探讨其对远端肺上皮细胞(DLEC)和原代培养的II型细胞的作用。采用双抗体夹心法测定内皮抑素水平。Luminex芯片检测BALF细胞因子和基质金属蛋白酶-3的表达。损伤原代DLEC单层，给予内皮抑素治疗。结果：与正常对照组相比，IPF患者BALF患者BALF和血浆中内皮抑素水平升高。内皮抑素、用力肺活量与气体转移量呈负相关。内皮抑素与多种促炎细胞因子和MMP3相关。生理剂量的内皮抑素可抑制DLEC创面修复44%，其作用部分依赖于FasL和caspase。内皮抑素使细胞凋亡率增加8%，细胞存活率降低34%。结论：IPF患者BALF中内皮抑素水平升高与多种细胞因子、MMP3和肺功能升高有关。内皮抑素是一种新型的DLEC创伤修复抑制剂，以FasL和caspase依赖的方式诱导细胞凋亡和降低细胞存活率。内皮抑素可能在特发性肺纤维化的异常上皮修复中发挥作用。
Background and aim: Aberrant angiogenesis and defective epithelial repair are key features of idiopathic pulmonary fibrosis (IPF). Endostatin is an antiangiogenic peptide with known effects on endothelial cells. This study aimed to establish the levels of endostatin in the bronchoalveolar lavage fluid (BALF) in IPF and to investigate its actions on distal lung epithelial cells (DLEC) and primary type II cells.Methods: 20 patients with IPF and 10 controls underwent BAL. Endostatin was measured by ELISA. BALF cytokines and matrix metalloproteinase (MMP)-3 were measured by Luminex array. Primary DLEC monolayers were wounded and treated with endostatin. Apoptosis and cell viability were assessed.Results: Endostatin was elevated in the BALF and plasma of patients with IPF compared with normal controls. There was a negative correlation between endostatin, forced vital capacity and gas transfer. Endostatin correlated with a number of proinflammatory cytokines and MMP3. Physiological endostatin doses inhibited DLEC wound repair by 44% in an effect that was partially FasL and caspase dependent. Endostatin increased apoptosis rates by 8% and reduced their viability by 34%. Similar effects of endostatin were seen in primary type II cells in terms of inhibition of wound repair and proliferation.Conclusions: Elevated BALF endostatin levels correlated with a number of elevated cytokines, MMP3 and lung function in IPF. Endostatin is a novel inhibitor of DLEC wound repair, inducing apoptosis and reducing cell viability in a FasL and caspase dependent manner. Endostatin may play a role in aberrant epithelial repair in IPF.