A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18
A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18
复制标题
DOI：
10.1164/rccm.200509-1518oc
复制
发表时间：
2006-04-01
影响因子：
24.7
通讯作者：
Zissel, G
中科院分区：
文献类型：
--
作者：
Prasse, A;Pechkovsky, DV;Zissel, G
理论基础：最近，巨噬细胞激活的模型已被修订。目的：研究人肺泡巨噬细胞(AM)对CC趋化因子配体18(CCL18)的表达和调节。方法：取69例特发性肺纤维化、结节病、过敏性肺炎患者和22例健康志愿者的肺泡灌洗液(BAL)。分别用定量逆转录聚合酶链式反应、原位杂交、流式细胞仪和免疫组织化学方法检测CCL18的表达。测量和主要结果：肺纤维化患者BAL来源的细胞自发产生CCL18明显增加，并与肺功能检测指标呈负相关。正常肺泡巨噬细胞经Th2细胞因子刺激和/或与人肺成纤维细胞共培养后，CCL18基因表达和蛋白合成上调。天然胶原通过β(2)-整合素/清道夫受体(S)介导的机制，显著上调Th2型细胞因子激活的正常AM中CCL18的表达。特发性肺纤维化患者肺泡巨噬细胞培养上清液可部分通过CCL18诱导正常肺成纤维细胞产生胶原。我们的发现表明，来自肺纤维化患者的AM揭示了一种交替激活的表型，并且可能是肺成纤维细胞持续纤维化过程的正反馈环路的一部分。
Rationale: Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated.Objectives: This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs).Methods: AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively.Measurements and Main Results: Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimulation and/or coculture with human lung fibroblasts. Native Collagen significantly up-regulated CCL18 expression in normal AMs activated with Th2 cytokines via a mechanism mediated by beta(2)-integrin/scavenger receptor(s). Culture supernatants of AMs from patients with idiopathic pulmonary fibrosis increased Collagen production by normal lung fibroblasts partly mediated via CCL18.Conclusions:. Our findings suggest that AMs from patients with pulmonary fibrosis disclose a phenotype of alternative activation and might be a part of a positive feedback loop with lung fibroblasts perpetuating fibrotic processes.