Protein biomarkers associated with primary graft dysfunction following lung transplantation

Abstract

Severe primary graft dysfunction affects 15-20% of lung transplant recipients and carries a high mortality risk. In addition to known donor, recipient, and perioperative clinical risk factors, numerous biologic factors are thought to contribute to primary graft dysfunction. Our current understanding of the pathogenesis of lung injury and primary graft dysfunction emphasizes multiple pathways leading to lung endothelial and epithelial injury. Protein biomarkers specific to these pathways can be measured in the plasma, bronchoalveolar lavage fluid, and lung tissue. Clarification of the pathophysiology and timing of primary graft dysfunction could illuminate predictors of dysfunction, allowing for better risk stratification, earlier identification of susceptible recipients, and development of targeted therapies. Here, we review much of what has been learned about the association of protein biomarkers with primary graft dysfunction and evaluate this association at different measurement time points.

Keywords: biomarkers; lung transplantation; primary graft dysfunction.

Fig. 1.

Representation of the time course, including ex vivo lung perfusion (EVLP), from the donor through to the postoperative period (clockwise direction), of biomarkers associated with primary graft dysfunction in the recipient. Biomarkers specific to the epithelium are shown centrally in the alveolus (orange print). Biomarkers specific to the vascular endothelium as well as coagulation, fibrinolysis, platelet activation, hypoxic injury, cell death markers and neutrophil activation are shown in the capillary lumen (blue print). Inflammatory cytokines are in red print. Epithelial markers: RAGE, receptor for advanced glycation end products; CC-16, club cell secretory protein; col(V), antibodies to collage type V; SP-D, surfactant protein D. Endothelial markers: ET-1, endothelin; big ET-1; NOx, nitric oxide metabolites; VEGF, vascular endothelial growth factor; Ang-2, angiopoietin 2; ICAM-1, intracellular adhesion molecule-1. Marker of hypoxic injury: proADM, proadrenomedullin. Cell death marker: CK18, cytokeratin 18. Marker of neutrophil activation: NETs, neutrophil extracellular traps. Markers of coagulation and fibrinolysis: PAI-1, plasminogen activator inhibitor 1; protein C. Marker of platelet activation: P-selectin. Markers of inflammation: IL, interleukin-6, 8, 10, 13, 1ra, and 2R; M-CSF, macrophage colony stimulating factor; G-CSF, granulocyte-colony stimulating factor; GRO-A, growth-regulated oncogene; MIP-1α and -1β, macrophage inflammatory protein-1α and -1β; MCP-1, monocyte chemoattractant protein; PTX3, long pentraxin-3; INF-α, interferon-α; IP, interferon-γ; MIG, monokine induced by interferon-γ.