Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury
Ciara M. Shaver, … , Lorraine B. Ware, the Lung Transplant Outcomes Group (LTOG)
Ciara M. Shaver, … , Lorraine B. Ware, the Lung Transplant Outcomes Group (LTOG)
Published January 25, 2018
Citation Information: JCI Insight. 2018;3(2):e98546. https://doi.org/10.1172/jci.insight.98546.
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Research Article Pulmonology Transplantation

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

Abstract

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.

Authors

Ciara M. Shaver, Nancy Wickersham, J. Brennan McNeil, Hiromasa Nagata, Adam Miller, Stuart R. Landstreet, Jamie L. Kuck, Joshua M. Diamond, David J. Lederer, Steven M. Kawut, Scott M. Palmer, Keith M. Wille, Ann Weinacker, Vibha N. Lama, Maria M. Crespo, Jonathan B. Orens, Pali D. Shah, Chadi A. Hage, Edward Cantu III, Mary K. Porteous, Gundeep Dhillon, John McDyer, Julie A. Bastarache, Jason D. Christie, Lorraine B. Ware, the Lung Transplant Outcomes Group (LTOG)

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Figure 5

Cell-free hemoglobin increased pulmonary edema formation and vascular permeability in ex vivo isolated perfused lungs.

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Cell-free hemoglobin increased pulmonary edema formation and vascular pe...
(A) Cell-free hemoglobin (CFH) added to the perfusate (100 mg/dl) in the presence of hyperoxia (FiO2 = 0.95) results in persistent weight gain over time, indicative of formation of pulmonary edema, n = 5 per group, *P = 0.047 vs. control. (B) CFH increased vascular permeability as evidenced by extravasation of Evans blue–labeled albumin into bronchoalveolar lavage fluid, n = 5 per group, *P = 0.027 vs. control at 2 hours. Comparisons were made between control and CFH groups by Mann Whitney U tests.