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 (RA) system, elicits fibrosis in both kidney and lung. We identified 6 AngII-regulated proteins (RHOB, BST1, LYPA1, GLNA, TSP1, LAMB1) increased in urine of patients with kidney allograft fibrosis. We hypothesized that RA 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) and TSP1/GLNA in 10 CLAD lungs and 5 controls. Using mass spectrometry, we quantified peptides corresponding to AngII-regulated proteins in BAL of 40 lung transplant recipients (CLAD, stable and acute lung allograft dysfunction (ALAD)). Machine learning algorithms were developed to predict CLAD based on BAL peptide concentrations.
Immunostaining demonstrated significantly more AGTR1+ cells in CLADversus控制肺(p = 0.02)。常会和GLNA immunostaining positively correlated with the degree of lung fibrosis (R2=0.42 and 0.57, respectively). In BAL, we noted a trend toward higher concentrations of AngII-regulated peptides in patients with CLAD at the time of bronchoscopy, and significantly higher concentrations of BST1, GLNA and RHOB peptides in patients that developed CLAD at follow-up (p<0.05). Support vector machine classifier discriminated CLAD from stable and ALAD patients at the time of bronchoscopy with AUC 0.86, and accurately predicted subsequent CLAD development (AUC 0.97).
Proteins involved in the RA system are increased in CLAD lung and BAL. AngII-regulated peptides measured in BAL may accurately identify patients with CLAD and predict subsequent CLAD development.
Footnotes
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Conflict of interest: Dr. Berra has nothing to disclose.
Conflict of interest: Dr. Farkona has nothing to disclose.
Conflict of interest: Dr. Mohammed-Ali has nothing to disclose.
Conflict of interest: Dr. Kotlyar has nothing to disclose.
Conflict of interest: Dr. Levy has nothing to disclose.
Conflict of interest: Mr Ly has nothing to disclose.
Conflict of interest: Dr. Guan has nothing to disclose.
Conflict of interest: Dr. Daigneault has nothing to disclose.
Conflict of interest: A. Duong has nothing to disclose.
Conflict of interest: I. Batruch has nothing to disclose.
利益冲突:Jurisica博士报告拨款and non-financial support from IBM, personal fees and other from Novartis, personal fees and other from Canadian Rheumatology Association, outside the submitted work.
Conflict of interest: Dr. Konvalinka has nothing to disclose.
Conflict of interest: Dr. Martinu reports grants from Canadian Donation and Transplantation Research Program, grants from Di Pochi funds, during the conduct of the study; grants from Sanofi, non-financial support from APCBio, outside the submitted work.
- ReceivedJuly 30, 2020.
- AcceptedMarch 6, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contactpermissions{at}ersnet.org