Abstract
Acute Respiratory Distress Syndrome (ARDS) continues to have a high mortality. Currently, there are no biomarkers that provide reliable prognostic information to guide clinical management or stratify risk among clinical trial participants. The objective of this study was to probe the bronchoalveolar lavage fluid (BALF) proteome to identify proteins that differentiate survivors from non-survivors of ARDS. Patients were divided into early-phase (1 to 7 days) and late-phase (8 to 35 days) groups based on time after initiation of mechanical ventilation for ARDS (Day 1). Isobaric tags for absolute and relative quantitation (iTRAQ) with LC MS/MS was performed on pooled BALF enriched for medium and low abundance proteins from early-phase survivors (n = 7), early-phase non-survivors (n = 8), and late-phase survivors (n = 7). Of the 724 proteins identified at a global false discovery rate of 1%, quantitative information was available for 499. In early-phase ARDS, proteins more abundant in survivors mapped to ontologies indicating a coordinated compensatory response to injury and stress. These included coagulation and fibrinolysis; immune system activation; and cation and iron homeostasis. Proteins more abundant in early-phase non-survivors participate in carbohydrate catabolism and collagen synthesis, with no activation of compensatory responses. The compensatory immune activation and ion homeostatic response seen in early-phase survivors transitioned to cell migration and actin filament based processes in late-phase survivors, revealing dynamic changes in the BALF proteome as the lung heals. Early phase proteins differentiating survivors from non-survivors are candidate biomarkers for predicting survival in ARDS.
Highlights
Acute Respiratory Distress Syndrome (ARDS) is characterized by the abrupt onset of tachypnea, hypoxia, and loss of lung compliance in response to infectious or inflammatory triggers [1]
The ProteinPilot PSPEP false discovery rate (FDR) Summary reported 20,601 spectra matched to 10,355 distinct peptides at #1% global FDR for a total of 792 inferred proteins (Table S1, Protein Pilot PSPEP summary and protein identified at 1% FDR tab)
These724 proteins were used as the background for GO enrichment analysis
Summary
Acute Respiratory Distress Syndrome (ARDS) is characterized by the abrupt onset of tachypnea, hypoxia, and loss of lung compliance in response to infectious or inflammatory triggers [1]. Most studies have focused on investigating an individual biomarker in blood, bronchoalveolar lavage fluid (BALF), or urine Markers of inflammation such as interleukin1b [23], interleukin 6 [7], and soluble TNF receptor I and II [24] are associated with poor prognosis in ARDS. Poorer outcomes are associated with higher plasma levels of SP-D (but not SP-A), a marker of type 2 alveolar epithelial cell damage [19], and receptor of advance glycation end products (RAGE), a marker of type 1 alveolar epithelial cell damage Several other molecules, such as those involved in coagulation [26], damage to extracellular matrix [20], and oxidative stress (urine NO) [20], correlate with ARDS outcomes. The identification of a single biomarker or a combination of biomarkers that could be widely used has remained elusive [28] due to lack of correlation between the biochemical marker, pathophysiological variables and clinical outcomes
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