Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis
Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis
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DOI：
10.1186/1465-9921-7-95
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发表时间：
2006-06-30
影响因子：
5.8
通讯作者：
Poletti, Venerino
中科院分区：
文献类型：
--
作者：
Chilosi, Marco;Zamo, Alberto;Poletti, Venerino
背景：成纤维细胞灶（FF）被认为是特发性肺纤维化/通常间质性肺炎（IPF/UIP）的相关形态学标志，被认为是这种严重疾病中纤维化反应启动和/或持续的部位。尽管它们具有相关性，但负责FF形成及其在组织重塑中的作用的细胞和分子机制尚不清楚。在之前的研究中，我们已经提供了IPF/UIP中wnt信号通路异常激活的证据，该通路以FF和上覆上皮为中心。这种重要的形态发生途径能够触发上皮-间质转化（EMT），这是一种参与发育和转移过程的机制，也可能参与肺纤维化。方法：由于EMT的特点是增强细胞的迁移潜力，我们研究了30例IPF/UIP活检组织和各种对照样本中FF的分子谱，重点研究了三种参与细胞运动和侵袭性的分子的免疫组织化学表达，即层粘胶蛋白- 5- γ 2链、束状蛋白和热休克蛋白-27。结果：我们提供的证据表明，在UIP中，这三种分子在精确定位于FF的细支气管基底细胞的离散簇中异常表达。这些细胞簇在非常高的水平上表达层粘连蛋白- 5- γ -2链和热休克蛋白-27，形成特征性的三层病变，定义为“三明治灶”（SW-FF）。定量分析表明，SW-FF存在于28/30的UIP样本中，占21/30中可识别FF的50%以上，但在作为对照检查的各种肺部病理中极为罕见。在UIP中，SW-FF经常在显微镜下的蜂窝区观察到，也在正常肺组织和致密疤痕区之间的界面上发现。结论：这些分子异常强烈提示SW-FF是肺重构的前沿，在这里发生异常迁移和再上皮化，细支气管基底细胞的异常增殖和迁移在IPF/UIP特征的重构过程中起主要作用。进一步的调查将评估它们作为可靠标记的可能性，以便更好地确定困难病例的upp模式。
Background: Fibroblast foci (FF) are considered a relevant morphologic marker of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), and are recognised as sites where fibrotic responses are initiated and/or perpetuated in this severe disease. Despite their relevance, the cellular and molecular mechanisms responsible for the formation of FF and their role in tissue remodelling are poorly defined. In previous studies we have provided evidence of abnormal activation of the wnt-signaling-pathway in IPF/UIP that is centred on FF and the overlying epithelium. This important morphogenetic pathway is able to trigger epithelial-mesenchymal-transition (EMT), a mechanism involved in developmental and metastatic processes, which is also potentially involved in pulmonary fibrosis.Methods: Since EMT is characterised by enhancement of migratory potential of cells, we investigated the molecular profile of FF in 30 biopsies of IPF/UIP and a variety of control samples, focussing on the immunohistochemical expression of three molecules involved in cell motility and invasiveness, namely laminin- 5-gamma 2-chain, fascin, and heat-shock-protein-27.Results: We provide evidence that in UIP these three molecules are abnormally expressed in discrete clusters of bronchiolar basal cells precisely localised in FF. These cellular clusters expressed laminin- 5-gamma 2-chain and heat-shock-protein-27 at very high levels, forming characteristic three-layered lesions defined as "sandwich-foci" (SW-FF). Upon quantitative analysis SW-FF were present in 28/30 UIP samples, representing more than 50% of recognisable FF in 21/30, but were exceedingly rare in a wide variety of lung pathologies examined as controls. In UIP, SW-FF were often observed in areas of microscopic honeycombing, and were also found at the interface between normal lung tissue and areas of dense scarring.Conclusion: These molecular abnormalities strongly suggest that SW-FF represent the leading edge of pulmonary remodelling, where abnormal migration and re-epithelialisation take place, and that abnormal proliferation and migration of bronchiolar basal cells have a major role in the remodelling process characterising IPF/UIP. Further investigations will assess their possible use as reliable markers for better defining the UIP-pattern in difficult cases.