CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling
CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling
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DOI：
10.1164/rccm.200409-1164oc
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发表时间：
2005-02-01
影响因子：
24.7
通讯作者：
Strieter, RM
中科院分区：
文献类型：
--
作者：
Burdick, MD;Murray, LA;Strieter, RM
异常血管重构是特发性肺纤维化发生和发展的中心标志。然而，病理生理学改变的机制还知之甚少。最近的干扰素γ-1b的11期试验表明，促纤维化和促血管生成生物标志物有减少的趋势，肺CXCL 11 mRNA和支气管肺泡灌洗液和CXCL 11血浆蛋白水平上调。我们假设，在博莱霉素诱导的肺纤维化过程中纤维增生和细胞外基质沉积的发病机制中观察到的净异常血管重塑可以通过用血管抑制性ELR-CXC趋化因子CXCL 11治疗来减弱。在临床前模型中，CXCL 11的全身给药减少了博来霉素处理的小鼠肺中的肺胶原沉积、前胶原基因表达和组织病理学纤维增生和细胞外基质沉积。CXCL 11治疗显著降低了博莱霉素诱导的肺纤维化，而不改变特定的肺白细胞群。CXCR 3在成纤维细胞上不表达，CXCL 11对肺成纤维细胞没有直接的功能作用。然而，肺中的血管生成活性显著降低，并且CXCL 11处理减少了博来霉素暴露后肺中内皮细胞的总数。结果表明，CXCL 11通过改变异常的血管重塑来抑制肺纤维化。
Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase 11 trial of interferon gamma-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-incluced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR- CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary Collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-incluced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.