Significant changes occurred in the urinary proteome, even when there were no clinical manifestations or histopathological damage to lung tissue, such as in a rat model of bleomycin-induced pulmonary fibrosis 20. Urinary proteomics studies have identified some candidate biomarkers for respiratory system disease, such as lung cancer 18, pulmonary fibrosis and tuberculosis 19, 20. In addition to the urinary system, urine can sensitively reflect changes in various systems throughout the body, such as cardiovascular system disease, gastrointestinal system disease, nervous system disease, and respiratory system disease 16, 17. Urine, as an attractive resource for biomarker research, can be collected noninvasively and continuously, which has attracted increasing attention. However, currently available biomarkers continue to lack sufficient validity to be incorporated into clinical practice for either the diagnosis or the prognosis of VILI. Despite the difficulties in identifying robust biomarkers, proteomics studies have identified important pathways in VILI, including endothelium injury and activation, epithelial injury, oxidative stress, inflammation, disordered repair of fibrosis and apoptosis 14, 15. Conversely, several proteomic analyses have assessed bronchoalveolar lavage fluid (BAL) fluid, which may be more relevant to lung pathology 12, 13 but are much more invasive and relatively harder to obtain. However, due to its high complexity and large dynamic range, performing proteomics assays with plasma is challenging. Proteomics studies of VILI biomarkers have overwhelmingly focused on serum/plasma, which is relatively easily obtained 10, 11. Mass-spectrometry-based proteomics has dramatically improved and emerged as a prominent tool in the field of biomarker studies. Therefore, it is of high importance to identify new biomarkers, therapeutic targets and pharmacological agents for VILI to decrease the morbidity and mortality associated with VILI. The mortality of patients with severe ARDS is 20% to 40%, and patients who survive are at high risk for cognitive decline, depression, posttraumatic stress disorder, and persistent skeletal muscle weakness 8, 9. In addition, 23% of all mechanically ventilated patients develop ARDS. All mechanically ventilated patients are at risk for VILI, especially when there're pathological changes in the lungs, such as acute respiratory distress syndrome (ARDS) 6, 7. However, mechanical ventilation may cause lung injury, called ventilator-induced lung injury (VILI) 3, 4, 5. Mechanical ventilation is an indispensable component of advanced life support strategies, especially for patients suffering from respiratory failure (from neonatal to adult patients) 1, 2. These differential proteins are potential urinary biomarkers for the activity of VILI. Our results suggest that the urinary proteome might reflect the pathophysiological changes associated with VILI. SLC31, MEP1A, S15A2, NHRF1, XPP2, GGT1, HEXA, and ATPB were newly discovered in this study. Among these PRM-validated proteins, AMPN, MEP1B, LYSC1, DPP4 and CYC were previously reported as lung-associated disease biomarkers. Finally, thirteen proteins were identified as candidate biomarkers for VILI by PRM validation. The canonical pathways and protein–protein interaction analyses revealed that the differentially expressed proteins were enriched in multiple functions, including oxidative stress and inflammatory responses. Compared to the control group, 110 proteins (65 upregulated, 45 downregulated) were significantly changed in the VILI group (1.5-fold change, P < 0.05). In total, 727 high-confidence proteins were identified with at least 1 unique peptide (FDR ≤ 1%). For further validation, the differential proteins were verified by parallel reaction monitoring (PRM)-targeted quantitative proteomics. In the discovery phase, a label-free data-dependent acquisition (DDA) quantitative proteomics method was used to profile the urinary proteomes of VILI rats. Therefore, the purpose of this study was to investigate potential urinary biomarkers to monitor the disease activity of ventilator-induced lung injury (VILI). Urine is a promising resource for biomarker research.
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