Abstract
Chronic lung allograft dysfunction (CLAD) is the major cause of death after lung transplantation. Angiotensin II (AngII), the main effector of the renin–angiotensin system, elicits fibrosis in both kidney and lung. We identified six AngII-regulated proteins (Ras homolog family member B (RHOB), bone marrow stromal cell antigen 1 (BST1), lysophospholipase 1 (LYPA1), glutamine synthetase (GLNA), thrombospondin 1 (TSP1) and laminin subunit β2 (LAMB2)) that were increased in urine of patients with kidney allograft fibrosis. We hypothesised that the renin–angiotensin system is active in CLAD and that AngII-regulated proteins are increased in bronchoalveolar lavage fluid (BAL) of CLAD patients.
We performed immunostaining of AngII receptors (AGTR1 and AGTR2), TSP1 and GLNA in 10 CLAD lungs and five controls. Using mass spectrometry, we quantified peptides corresponding to AngII-regulated proteins in BAL of 40 lung transplant recipients (stable, acute lung allograft dysfunction (ALAD) and CLAD). Machine learning algorithms were developed to predict CLAD based on BAL peptide concentrations.
Immunostaining demonstrated significantly more AGTR1+细胞中的细胞versus控制肺(p = 0.02)。TSP1和GLNA免疫染色与肺纤维化程度正相关(R2分别= 0.42和0.57)。在BAL中,我们指出了在支气管镜检查时具有外壳患者的浓度较高的血管杆菌调节肽的趋势,并且在随访时出现clad的患者中,BST1,GLNA和RHOB肽的浓度明显更高(P <0.05)(P <0.05)(P <0.05)。支撑矢量机分类器在支气管镜检查时(曲线下(AUC)0.86)的稳定患者和ALAD患者区分了外壳,并准确地预测了随后的外壳发育(AUC 0.97)。
Proteins involved in the renin–angiotensin system are increased in CLAD lungs and BAL. AngII-regulated peptides measured in BAL may accurately identify patients with CLAD and predict subsequent CLAD development.
Abstract
Components of the renin–angiotensin system are increased in chronic lung allograft dysfunction (CLAD) fibrosis. Angiotensin II-regulated proteins in bronchoalveolar lavage identify concurrent and predict future CLAD in lung transplant recipients.https://bit.ly/3eRYez7
Footnotes
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作者贡献:G。Berra:临床筛查,队列设计,样本收集和组织,免疫染色,QPCR,Western印迹,数据分析,手稿的写作。S. Farkona:实验设计,质谱,蛋白质印迹,数据分析,手稿撰写。Z. Mohammed-Ali:质谱法。M. Kotlyar:生物信息学分析,机器学习算法,手稿写作。L. Levy:队列设计,收集和处理样品,帮助手稿写作。S. Clotet-Freixas:Western印迹。P. Ly:免疫染色。B. Renaud-Picard:临床筛查,样品收集,组织学分级。G. Zehong:免疫染色方案的帮助。T. Daigneault:样品收集。 A. Duong: collection and organisation of samples. I. Batruch: technical assistance with mass spectrometry. I. Jurisica: protein interactome generation, bioinformatic analyses supervision. A. Konvalinka and T. Martinu: conception of the research question, cohort design, experimental design, supervision of experiments, data analysis, manuscript writing and editing.
利益冲突:G。Berra无话可说。
利益冲突:S。Farkona无话可说。
Conflict of interest: Z. Mohammed-Ali has nothing to disclose.
利益冲突:科特里尔先生没有什么可披露的。
利益冲突:L。Levy无话可说。
利益冲突:S。Clotet-Freixas没有什么可披露的。
Conflict of interest: P. Ly has nothing to disclose.
利益冲突:B。Renaud-Picard没有什么可披露的。
利益冲突:G。Zehong没有什么可披露的。
Conflict of interest: T. Daigneault has nothing to disclose.
利益冲突:A。Duong无话可说。
利益冲突:I。Batruch没有什么可披露的。
Conflict of interest: I. Jurisica reports grants and nonfinancial support (in-kind contribution to grants) from IBM, personal fees for lectures and other (reimbursement of expenses) from Novartis and Canadian Rheumatology Association, outside the submitted work.
利益冲突:A。Konvalinka没有什么可披露的。
Conflict of interest: T. Martinu reports grants from Canadian Donation and Transplantation Research Program and Di Pochi funds, during the conduct of the study; grants from Sanofi, nonfinancial support from APCBio, outside the submitted work.
Support statement: The authors disclose receipt of the following financial support for this research: Canadian National Transplant Research Program, Kidney Foundation of Canada Predictive Biomarker Grant, Canadian Institute for Health Research (CIHR), Kidney Research Scientist Core Education, National Training (KRESCENT) program, Di Pochi funds, Toronto General and Western Hospital Foundation, University Health Network Multi Organ Transplant Program, and Les Hôpitaux Universitaires de Genève. Computational analyses were supported in part by grants from the Ontario Research Fund (34876) and Canada Foundation for Innovation (29272, 225404 and 33536). Funding information for this article has been deposited with theCrossRef资助人注册表。
- ReceivedJuly 30, 2020.
- 公认March 6, 2021.
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