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Proteomic Analysis of Infants Undergoing Cardiopulmonary Bypass Using Contemporary Ontological Tools
Christopher Robert Reed1, Christopher Cameron McCoy2, Uttara Nag1
1Department of Surgery, Duke University Medical Center, Durham, North Carolina.
Insights
Infants undergoing cardiopulmonary bypass (CPB) show complex immune and coagulation responses. Proteomic analysis reveals key protein networks influencing hemostasis and inflammation in pediatric CPB patients.
Area of Science:
- Pediatric Cardiology
- Proteomics
- Biochemistry
Background:
- Cardiopulmonary bypass (CPB) is critical for infant congenital heart defect repair but causes significant hemostasis and inflammation issues.
- Hemorrhagic complications and thrombosis are major challenges in pediatric CPB and ECMO management.
- Conventional tests fail to capture complex interactions in coagulation, fibrinolysis, and inflammation.
Purpose of the Study:
- To utilize unbiased proteomic analysis to identify protein interaction networks in pediatric CPB.
- To investigate complex hemostatic and inflammatory derangements associated with CPB in infants.
Main Methods:
- Plasma samples collected from infants (up to 1 year) at 0, 4, and 24 hours post-CPB.
- Two-dimensional difference gel electrophoresis and mass spectrometry used to identify protein concentration changes.
- STRING and ToppGene tools employed for biological network identification; ELISA for inflammatory markers.
Main Results:
- Over 1400 protein spots analyzed; 89 proteins showed >30% concentration change (P < 0.02).
- Mass spectrometry identified 29 differentially expressed proteins, dominated by acute phase response, coagulation, and cell signaling.
- Elevated IL-2, IL-8, IL-10 at 4h post-CPB, with persistent IL-6 elevation; normalized by 24h.
Conclusions:
- Infants exhibit a robust, complex response to CPB involving overlapping immune, coagulation, and cell signaling pathways.
- Further research into these interacting systems may yield novel therapeutics and biomarkers for pediatric CPB management.
Background:
Cardiopulmonary bypass (CPB) is essential for the repair of many congenital cardiac defects in infants but is associated with significant derangements in hemostasis and systemic inflammation. As a result, hemorrhagic complications and thrombosis are major challenges in the management of children requiring CPB or extracorporeal membrane oxygenation. Conventional clinical laboratory tests capture individual hemostatic derangements (low platelets, elevated fibrinogen) but fail to describe the complex, overlapping interactions among the various components of coagulation, including cellular interactions, contact activation, fibrinolysis, and inflammation. Given recent advances in analytic tools for identifying protein-protein interactions in the plasma proteome, we hypothesized that an unbiased proteomic analysis would help identify networks of interacting proteins for further investigation in pediatric CPB.
Materials And Methods:
Infants up to 1 y of age were enrolled. Plasma samples were collected at 0, 1, 4, and 24 h after CPB. Mass spectrometry was used to identify proteins undergoing changes in concentration after CPB, and STRING and ToppGene tools were used to identify biological networks. Two-dimensional difference gel electrophoresis identified changes in protein concentrations. Inflammatory markers were assessed by enzyme-linked immunosorbent assay at the same time points.
Results:
Ten infants with cardiac anomalies requiring surgery and CPB were enrolled; no major complications were recorded (median age, 127.5 d; interquartile range, 181.25 d). Using two-dimensional difference gel electrophoresis, >1400 individual protein spots were observed, and 89 proteins demonstrated change in concentration >30% with P < 0.02 when comparing 1, 4, or 24 h to baseline. Among protein spots with significant changes in concentration after CPB, 29 were identified with mass spectrometry (33%). In our interrogation of functional associations among these differentially expressed proteins, our results were dominated by the acute phase response, coagulation, and cell signaling functional categories. Among cytokines analyzed by enzyme-linked immunosorbent assay, IL-2, IL-8, and IL-10 were elevated at 4 h but normalized by 24 h, whereas IL-6 was persistently elevated.
Conclusions:
Infants manifest a robust response to CPB that includes overlapping, complex pathways. Further investigation of interactions among immune, coagulation, and cell signaling systems may lead to novel therapeutics or biomarkers useful in the management of infants requiring CPB.
