Extracellular histones play a pathogenic role in primary graft dysfunction after human lung transplantation

Primary graft dysfunction (PGD) causes early mortality and late graft failure after lung transplantation. The mechanisms of PGD are not fully understood but ischemia/reperfusion (I/R) injury may be involved. Extracellular histones have recently been identified as major contributors to I/R injury. Hence, we investigated whether extracellular histones are associated with PGD after lung transplantation. In total, 65 lung transplant patients were enrolled into this study. Blood samples were collected from patients before and serially after transplantation (24 h, 48 h, and 72 h) and measured for extracellular histones, myeloperoxidase (MPO), lactate dehydrogenase (LDH), and multiple cytokines. Besides, the patients' sera were cultured with human pulmonary artery endothelial cells (HPAEC) and human monocyte cell line (THP1) cells, respectively, and cellular viability and cytokine production were determined. Heparin or anti-histone antibody were used to study the effects of histone-neutralized interventions. The results showed that extracellular histones increased markedly after lung transplantation, peaked by 24 h and tended to decrease thereafter, but still retained high levels up to 72 h. Extracellular histones were more abundant in patients with PGD (n = 8) than patients without PGD (n = 57) and linearly correlated with MPO, LDH, and most detected cytokines. Ex vivo studies showed that the patients' sera collected within 24 h after transplantation were very damaging to HPAEC cells and promoted cytokine production in cultured THP1 cells, which could be largely prevented by heparin or anti-histone antibodies. These data suggested a pathogenic role for extracellular histones in PGD after lung transplantation. Targeting extracellular histones may serve as a preventive and therapeutic strategy for PGD following lung transplantation.