Proteomic Analysis of Primary Graft Dysfunction in Porcine Lung Transplantation Reveals Alveolar-Capillary Barrier Changes Underlying the High Particle Flow Rate in Exhaled Breath.

Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by 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. Recipients with PGD had significantly higher PFR [686.4 (449.7-8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7-307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD.

Exhaled phospholipid transfer protein and hepatocyte growth factor receptor in lung adenocarcinoma.

BACKGROUND: Screening decreases mortality among lung cancer patients but is not widely implemented, thus there is an unmet need for an easily accessible non-invasive method to enable early diagnosis. Particles in exhaled air offer a promising such diagnostic tool. We investigated the validity of a particles in exhaled air device (PExA) to measure the particle flow rate (PFR) and collect exhaled breath particles (EBP) to diagnose primary lung adenocarcinoma (LUAD). METHODS: Seventeen patients listed for resection of LUAD stages IA-IIIA and 18 non-cancer surgical control patients were enrolled. EBP were collected before and after surgery for LUAD, and once for controls. Proteomic analysis was carried out using a proximity extension assay technology. Results were validated in both plasma from the same cohort and with microarray data from healthy lung tissue and LUAD tissue in the GSE10072 dataset. RESULTS: Of the 92 proteins analyzed, levels of five proteins in EBP were significantly higher in the LUAD patients compared to controls. Levels of phospholipid transfer protein (PLTP) and hepatocyte growth factor receptor (MET) decreased in LUAD patients after surgery compared to control patients. PFR was significantly higher in the LUAD cohort at all timepoints compared to the control group. MET in plasma correlated significantly with MET in EBP. CONCLUSION: Collection of EBP and measuring of PFR has never been performed in patients with LUAD. In the present study PFR alone could distinguish between LUAD and patients without LUAD. PLTP and MET were identified as potential biomarkers to evaluate successful tumor excision.

New insight: particle flow rate from the airways as an indicator of cardiac failure in the intensive care unit.

AIMS: Exhaled breath particles have been explored for diagnosing different lung diseases. We recently showed in an experimental model that different cardiac output results in different particle flow rate (PFR) from the airways. Given the well-known close relationship between impaired cardiac function and respiratory failure, we hypothesized that PFR in exhaled air can be used to detect cardiac failure. METHODS: PFR was analysed using a customized PExA device. Particles in the range of 0.41-4.55 µm were measured. The included patients (n = 20) underwent cardiac surgery and received mechanical ventilation as a part of routine post-operative care. Ten patients with clinical signs of pronounced post-operative haemodynamic instability and need for inotrope or mechanical support had been selected to the cardiac failure group. The control group consisted of 10 patients without signs of cardiac failure. RESULTS: The patients in cardiac failure group required inotropic support in the form of dobutamine (9/10), epinephrine (2/10), or levosimendan (4/10) or use of an intra-aortic balloon pump (4/10). There was no use of inotropes or mechanical support devices among the controls. All patients in the cardiac failure group had pre-operative left ventricular ejection fraction ≤40% compared with the control group, whose pre-operative ejection fraction was ≥50%, P < 0.001. Patients with cardiac failure had significantly longer median total time in mechanical ventilation compared with the patients in the control group: 53.5 h (IQR 6.8-116101.0 h) and 4.5 h (IQR 4.0-5.5 h), respectively, P < 0.001, and the median length of stay in the ICU, 165 h (IQR 28-192 h) and 22 h (IQR 20-23.5 h), respectively, P = 0.007. Median PFR in patients with cardiac failure was higher than PFR in those with normal cardiac function: 80.9 particles/min (interquartile range (IQR) 25.8-336.6 particles/min), vs. 15.3 particles/min (IQR 8.1-17.7 particles/min), respectively, P < 0.001. Median particle mass was 8.95 ng (IQR 1.68-41.73 ng) in the cardiac failure group and 0.75 ng (IQR 0.18-1.45 ng) in the control group, P = 0.002. CONCLUSIONS: Patients with post-operative cardiac failure following cardiac surgery exhibited an increase in exhaled particle mass and PFR compared with the control group, indicating a significant difference between those two groups. The increase in particle mass and PFR in the absence of respiratory pathologies may indicate cardiac failure. In comparison with controls, impaired cardiac function was also associated with different composition of the particles regarding their size distribution.