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

Published online

Journal Article

Primary graft dysfunction (PGD) is acute lung injury within 72 hours of lung transplantation. We hypothesized that cell-free hemoglobin (CFH) contributes to PGD by increasing lung microvascular permeability and tested this in patients, ex vivo human lungs, and cultured human lung microvascular endothelial cells. In a nested case control study of 40 patients with severe PGD at 72 hours and 80 matched controls without PGD, elevated preoperative CFH was independently associated with increased PGD risk (odds ratio [OR] 2.75, 95%CI, 1.23-6.16, P = 0.014). The effect of CFH on PGD was magnified by reperfusion fraction of inspired oxygen (FiO2) ≥ 0.40 (OR 3.41, P = 0.031). Isolated perfused human lungs exposed to intravascular CFH (100 mg/dl) developed increased vascular permeability as measured by lung weight (CFH 14.4% vs. control 0.65%, P = 0.047) and extravasation of Evans blue-labeled albumin dye (EBD) into the airspace (P = 0.027). CFH (1 mg/dl) also increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers (hPMVECs). Hyperoxia (FiO2 = 0.95) increased human lung and hPMVEC permeability compared with normoxia (FiO2 = 0.21). Treatment with acetaminophen (15 μg/ml), a specific hemoprotein reductant, prevented CFH-dependent permeability in human lungs (P = 0.046) and hPMVECs (P = 0.037). In summary, CFH may mediate PGD through oxidative effects on microvascular permeability, which are augmented by hyperoxia and abrogated by acetaminophen.

Full Text

Duke Authors

Cited Authors

  • Shaver, CM; Wickersham, N; McNeil, JB; Nagata, H; Miller, A; Landstreet, SR; Kuck, JL; Diamond, JM; Lederer, DJ; Kawut, SM; Palmer, SM; Wille, KM; Weinacker, A; Lama, VN; Crespo, MM; Orens, JB; Shah, PD; Hage, CA; Cantu, E; Porteous, MK; Dhillon, G; McDyer, J; Bastarache, JA; Christie, JD; Ware, LB; Lung Transplant Outcomes Group (LTOG),

Published Date

  • January 25, 2018

Published In

Volume / Issue

  • 3 / 2

PubMed ID

  • 29367464

Pubmed Central ID

  • 29367464

Electronic International Standard Serial Number (EISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.98546

Language

  • eng

Conference Location

  • United States