Proteomic analysis of primary graft dysfunction and high particle flow rate

Background: Primary graft dysfunction (PGD) remains a challenge to lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for the rapid detection of PGD and the measurement of particle flow rate (PFR) from exhaled breath is a novel means to monitor disease. Methods: 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on the third post-operative day. Exhaled breath particles (EBPs) and PFR were measured on mechanical ventilation. EBPs were evaluated with mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Results: 9 recipients developed PGD and had significantly higher PFR (686.4 (449.7-8824.0) particles per minute (ppm)) compared to recipients without PGD (116.6 (79.7-307.4) ppm, p=0.0005). From proteomic analysis, porcine and human EBP proteins recapitulated the BAL and adherens and tight junction proteins were underexpressed in PGD tissue. Conclusions: Histological and proteomic analysis found significant changes to the alveolar-capillary barrier to explain the increased PFR in recipients with PGD. Combined with the similarity of proteomic profiles between EBPs and BALF, exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD.