气道嗜酸性粒细胞在哮喘气道重塑中的作用：MMP-10和MET的作用
2019/04/19
摘要
背景：嗜酸性粒细胞在哮喘的病理生理中起重要作用，涉及气道上皮损伤和气道重塑。我们确定了与哮喘患者气道重塑和嗜酸性粒细胞炎症相关的基因。
方法：我们分析了81例U-BIOPRED队列中-重度哮喘患者支气管活检组织的转录组学数据。使用Affymetrix阵列对总RNA进行表达谱分析。转录结合位点分析使用PRIMA算法。通过免疫组织化学定位蛋白质。
结果：使用严格的错误发现率分析，与粘膜低嗜酸性粒细胞（LE）相比，MMP-10和MET在粘膜高嗜酸性粒细胞（HE）的活组织检查中显著表达。免疫组织化学证实在哮喘患者组织活检中，支气管上皮细胞、上皮下炎症和固有细胞中MMP-10和MET的表达增加。使用较不严格的条件（原始P值<0.05，log2倍变化> 0.5），我们定义了与LE组相比HE的73基因组特征。73个基因中的33个驱动了通路注释，包括细胞外基质（ECM）组织，肥大细胞活化，CC-趋化因子受体结合，循环免疫球蛋白复合物，丝氨酸蛋白酶抑制剂和微管束形成途径。参与ECM组织的基因包括MET和MMP10与粘膜下层厚度呈正相关。转录因子结合位点分析确定了两种转录因子，即ETS-1和SOX家族蛋白，其与MMP10和MET表达呈正相关。
结论：气道重塑和细胞炎症途径与粘膜下嗜酸性粒细胞增多相关。MET和MMP-10可能在这些过程中起重要作用。
Kuo CS, Pavlidis, Zhu J, Loza M, Baribaud F, Rowe A, Pandis I, Gibeon D, Hoda U, Sousa A, Wilson SJ, Howarth P, Shaw D, Fowler S, Dahlen B, Chanez P, Krug N, Sandstrom T, Fleming L, Corfield J, Auffray C, Djukanovic R, Sterk PJ, Guo Y, Adcock IM, Chung KF; U-BIOPRED Project Team.
Abstract
BACKGROUND: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma.
METHODS: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry.
RESULTS: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression.
CONCLUSION: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
背景：嗜酸性粒细胞在哮喘的病理生理中起重要作用，涉及气道上皮损伤和气道重塑。我们确定了与哮喘患者气道重塑和嗜酸性粒细胞炎症相关的基因。
方法：我们分析了81例U-BIOPRED队列中-重度哮喘患者支气管活检组织的转录组学数据。使用Affymetrix阵列对总RNA进行表达谱分析。转录结合位点分析使用PRIMA算法。通过免疫组织化学定位蛋白质。
结果：使用严格的错误发现率分析，与粘膜低嗜酸性粒细胞（LE）相比，MMP-10和MET在粘膜高嗜酸性粒细胞（HE）的活组织检查中显著表达。免疫组织化学证实在哮喘患者组织活检中，支气管上皮细胞、上皮下炎症和固有细胞中MMP-10和MET的表达增加。使用较不严格的条件（原始P值<0.05，log2倍变化> 0.5），我们定义了与LE组相比HE的73基因组特征。73个基因中的33个驱动了通路注释，包括细胞外基质（ECM）组织，肥大细胞活化，CC-趋化因子受体结合，循环免疫球蛋白复合物，丝氨酸蛋白酶抑制剂和微管束形成途径。参与ECM组织的基因包括MET和MMP10与粘膜下层厚度呈正相关。转录因子结合位点分析确定了两种转录因子，即ETS-1和SOX家族蛋白，其与MMP10和MET表达呈正相关。
结论：气道重塑和细胞炎症途径与粘膜下嗜酸性粒细胞增多相关。MET和MMP-10可能在这些过程中起重要作用。
（中日友好医院呼吸与危重症医学科 张 鑫 摘译 林江涛 审校）
（Allergy. 2019 Jan 22. doi: 10.1111/all.13727.）
Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET.（Allergy. 2019 Jan 22. doi: 10.1111/all.13727.）
Kuo CS, Pavlidis, Zhu J, Loza M, Baribaud F, Rowe A, Pandis I, Gibeon D, Hoda U, Sousa A, Wilson SJ, Howarth P, Shaw D, Fowler S, Dahlen B, Chanez P, Krug N, Sandstrom T, Fleming L, Corfield J, Auffray C, Djukanovic R, Sterk PJ, Guo Y, Adcock IM, Chung KF; U-BIOPRED Project Team.
Abstract
BACKGROUND: Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma.
METHODS: We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry.
RESULTS: Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression.
CONCLUSION: Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.
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哮喘中的细胞因子
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通过气道蛋白质组学特征对哮喘表型进行分层
