Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

Area of Science:

• Pulmonary Medicine
• Transplantation Immunology
• Vascular Biology

Background:

• Primary graft dysfunction (PGD) is a major complication following lung transplantation, characterized by acute lung injury within 72 hours.
• The precise mechanisms underlying PGD pathogenesis, particularly the role of microvascular injury, require further elucidation.

Purpose of the Study:

• To investigate the role of cell-free hemoglobin (CFH) in the development of PGD.
• To determine if CFH increases lung microvascular permeability and if this effect is modulated by hyperoxia.
• To evaluate the potential of acetaminophen as a therapeutic agent to mitigate CFH-induced lung injury.

Main Methods:

• A nested case-control study analyzed preoperative CFH levels in lung transplant recipients with and without PGD.
• Ex vivo perfusion of human lungs exposed to CFH and hyperoxia (FiO2 ≥ 0.40).
• In vitro studies using cultured human pulmonary microvascular endothelial cells (hPMVECs) treated with CFH and hyperoxia.

Main Results:

• Elevated preoperative CFH was independently associated with an increased risk of severe PGD (OR 2.75).
• The risk of PGD was magnified by reperfusion hyperoxia (FiO2 ≥ 0.40).
• Ex vivo lungs and hPMVECs exposed to CFH exhibited increased vascular permeability, which was exacerbated by hyperoxia.
• Acetaminophen treatment abrogated CFH-dependent permeability in both human lungs and hPMVECs.

Conclusions:

• Cell-free hemoglobin may contribute to PGD by inducing oxidative damage to lung microvascular endothelial cells, increasing permeability.
• Hyperoxia potentiates CFH-mediated lung injury.
• Acetaminophen demonstrates potential as a therapeutic intervention to counteract CFH-induced PGD.