哮喘患者气道中的成纤维细胞表现为浸润表型
2011/06/17
摘要
原理：在细胞的恶性转化中观察到细胞浸润性表型，但其他疾病（包括哮喘）尚未观察到该现象。研究发现，细胞的浸润性是由转化生长因子β1(TGFβ1)和基质金属蛋白酶（MMPs）介导的。白介素13(IL-13)是一个重要的Th2细胞因子，通过TGFβ1和MMPs介导了气道重构的一些特征。
目的：我们认为，对于人体哮喘，与正常个体相比，IL-13能通过TGFβ1和MMPs增加气道成纤维细胞的浸润性。
方法：对进行支气管镜检查的20名轻度哮喘患者（(FEV1: 90 ± 3.6%预测值）和17名正常对照（FEV1: 102 ± 2.9%预测值)，收集支气管标本，分离并培养成纤维细胞。采用侵袭室(Matrigel chambers)检测成纤维细胞的浸润性。IL-13、IL-13联合TGF-β1中和抗体或MMP非选择性抑制剂(GM6001)加入培养下室作为趋化剂。来自于某些个体的细胞采用流式细胞仪和免疫组化检测IL-13受体水平。
检测指标和主要结果：与正常对照相比，IL-13能显著刺激哮喘患者气道成纤维细胞的浸润。TGFβ1抑制剂和MMPs抑制剂能阻断IL-13诱导的哮喘患者气道成纤维细胞浸润性，但对正常个体的气道成纤维细胞无影响。在基线状态下，与正常对照相比，哮喘患者的气道组织呈现IL-13高表达。与正常成纤维细胞相比，哮喘患者的气道成纤维细胞，基线状态下IL-13Rα2显著下降。
结论：IL-13通过TGF-β1和MMPs依赖的方式增加气道成纤维细胞的浸润性。IL-13受体亚单位在哮喘患者存在差异性表达。这些因素最终导致哮喘患者IL-13介导的气道重构。
（刘国梁 审校）
Am J Respir Crit Care Med. 2011 Mar 25. [Epub ahead of print]
Airway Fibroblasts in Asthma Manifest an Invasive Phenotype.
Ingram JL, Huggins MJ, Church TD, Li Y, Francisco DC, Degan S, Firszt R, Beaver DM, Lugogo NL, Wang Y, Sunday ME, Noble PW, Kraft M.
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States.
Abstract
RATIONALE: Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor beta-1 (TGFβ1) and matrix metalloproteinases (MMPs). Interleukin-13 (IL-13) is a key TH2 cytokine that directs many features of airway remodeling through TGFβ1 and MMPs.
OBJECTIVES: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGFβ1 and MMPs in asthma as compared to normal controls.
METHODS: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV1: 90 ± 3.6% pred) and 17 normal controls (FEV1: 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels.
MEASUREMENTS AND MAIN RESULTS: IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, as compared to normal controls. Inhibitors of both TGFβ1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal controls. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, as compared to normal controls. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared to normal controls.
CONCLUSIONS: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.
Am J Respir Crit Care Med. 2011 Mar 25. [Epub ahead of print]
原理：在细胞的恶性转化中观察到细胞浸润性表型，但其他疾病（包括哮喘）尚未观察到该现象。研究发现，细胞的浸润性是由转化生长因子β1(TGFβ1)和基质金属蛋白酶（MMPs）介导的。白介素13(IL-13)是一个重要的Th2细胞因子，通过TGFβ1和MMPs介导了气道重构的一些特征。
目的：我们认为，对于人体哮喘，与正常个体相比，IL-13能通过TGFβ1和MMPs增加气道成纤维细胞的浸润性。
方法：对进行支气管镜检查的20名轻度哮喘患者（(FEV1: 90 ± 3.6%预测值）和17名正常对照（FEV1: 102 ± 2.9%预测值)，收集支气管标本，分离并培养成纤维细胞。采用侵袭室(Matrigel chambers)检测成纤维细胞的浸润性。IL-13、IL-13联合TGF-β1中和抗体或MMP非选择性抑制剂(GM6001)加入培养下室作为趋化剂。来自于某些个体的细胞采用流式细胞仪和免疫组化检测IL-13受体水平。
检测指标和主要结果：与正常对照相比，IL-13能显著刺激哮喘患者气道成纤维细胞的浸润。TGFβ1抑制剂和MMPs抑制剂能阻断IL-13诱导的哮喘患者气道成纤维细胞浸润性，但对正常个体的气道成纤维细胞无影响。在基线状态下，与正常对照相比，哮喘患者的气道组织呈现IL-13高表达。与正常成纤维细胞相比，哮喘患者的气道成纤维细胞，基线状态下IL-13Rα2显著下降。
结论：IL-13通过TGF-β1和MMPs依赖的方式增加气道成纤维细胞的浸润性。IL-13受体亚单位在哮喘患者存在差异性表达。这些因素最终导致哮喘患者IL-13介导的气道重构。
（刘国梁 审校）
Am J Respir Crit Care Med. 2011 Mar 25. [Epub ahead of print]
Airway Fibroblasts in Asthma Manifest an Invasive Phenotype.
Ingram JL, Huggins MJ, Church TD, Li Y, Francisco DC, Degan S, Firszt R, Beaver DM, Lugogo NL, Wang Y, Sunday ME, Noble PW, Kraft M.
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States.
Abstract
RATIONALE: Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor beta-1 (TGFβ1) and matrix metalloproteinases (MMPs). Interleukin-13 (IL-13) is a key TH2 cytokine that directs many features of airway remodeling through TGFβ1 and MMPs.
OBJECTIVES: We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGFβ1 and MMPs in asthma as compared to normal controls.
METHODS: Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV1: 90 ± 3.6% pred) and 17 normal controls (FEV1: 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels.
MEASUREMENTS AND MAIN RESULTS: IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, as compared to normal controls. Inhibitors of both TGFβ1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal controls. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, as compared to normal controls. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared to normal controls.
CONCLUSIONS: IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.
Am J Respir Crit Care Med. 2011 Mar 25. [Epub ahead of print]
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