T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction
T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction
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DOI：
10.1111/ajt.14166
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发表时间：
2017-06-01
影响因子：
8.8
通讯作者：
Magnan, A.
中科院分区：
文献类型：
--
作者：
Pain, M.;Royer, P. -J.;Magnan, A.
慢性肺移植物功能障碍（CLAD）是肺移植术后长期生存的主要限制因素。CLAD表现为闭塞性细支气管炎综合征（BOS）或限制性同种异体移植综合征（RAS）。同种异体免疫反应和上皮间质转化已被建议在BOS。然而，很少有人知道关于上皮细胞分化的同种异体的作用。在存在或不存在转化生长因子（TGF）-β的情况下，用活化的T细胞处理原代人支气管上皮细胞（BEC）。观察上皮细胞和间质细胞标志物的表达。炎症细胞因子和基质金属蛋白酶（MMP）-9的分泌测定培养上清液和血浆中的肺移植受体（LTR）：49稳定，29与BOS，16与RAS。我们证明了由T细胞分泌的C-C基序趋化因子2在与C-C趋化因子受体2型结合后支持TGF-β诱导的BEC产生MMP-9。LTR的纵向研究显示CLAD发作前血浆MMP-9升高。多变量分析显示，血浆MMP-9与BOS（OR = 6.19，p = 0.002）或RAS（OR = 3.9，p = 0.024）独立相关，并预测功能诊断前12个月CLAD的发生。因此，免疫细胞通过产生MMP-9支持气道重塑。血浆MMP-9是CLAD的潜在预测生物标志物。
Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-beta. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-beta-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.