Association between the renin-angiotensin system and chronic lung allograft dysfunction

Area of Science:

• Transplantation immunology
• Renal and pulmonary fibrosis research
• Biomarker discovery in lung allografts

Background:

• Chronic lung allograft dysfunction (CLAD) is a primary cause of mortality post-lung transplantation.
• The renin-angiotensin system (RAS) and its effector Angiotensin II (AngII) are implicated in fibrotic processes in both renal and pulmonary systems.
• Previous studies identified AngII-regulated proteins in urine associated with kidney allograft fibrosis.

Purpose of the Study:

• To investigate the activity of the renin-angiotensin system in CLAD.
• To determine if AngII-regulated proteins are elevated in bronchoalveolar lavage fluid (BAL) of CLAD patients.
• To develop predictive models for CLAD using BAL peptide concentrations.

Main Methods:

• Immunostaining for AngII receptors (AGTR1, AGTR2), TSP1, and GLNA in CLAD and control lung tissues.
• Mass spectrometry-based quantification of AngII-regulated protein peptides in BAL fluid from lung transplant recipients.
• Development of machine learning algorithms to predict CLAD status and development.

Main Results:

• Increased AGTR1-positive cells observed in CLAD lungs compared to controls.
• TSP1 and GLNA immunostaining correlated positively with lung fibrosis severity.
• Elevated concentrations of BST1, GLNA, and RHOB peptides in BAL fluid of patients who developed CLAD.
• Machine learning models achieved high accuracy in discriminating CLAD and predicting future CLAD development (AUC 0.86 and 0.97, respectively).

Conclusions:

• Proteins regulated by AngII are increased in CLAD lungs and BAL fluid.
• AngII-regulated peptides in BAL fluid show potential as biomarkers for identifying CLAD.
• BAL peptide analysis may predict the subsequent development of CLAD in lung transplant recipients.