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

Lung Transplant Outcomes Group (LTOG)

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number2
DOIs
StatePublished - Jan 25 2018

Fingerprint

Primary Graft Dysfunction
Lung Injury
Hemoglobins
Lung
Capillary Permeability
Endothelial Cells
Permeability
Hyperoxia
Odds Ratio
Acetaminophen
Evans Blue
Lung Transplantation
Acute Lung Injury
Reducing Agents
Reperfusion
Case-Control Studies
Albumins

Keywords

  • endothelial cells
  • Organ transplantation
  • Pulmonology
  • Respiration
  • Transplantation

Cite this

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury. / Lung Transplant Outcomes Group (LTOG).

In: JCI insight, Vol. 3, No. 2, 25.01.2018.

Research output: Contribution to journalArticle

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

AU - Shaver, Ciara M.

AU - Wickersham, Nancy

AU - McNeil, J. Brennan

AU - Nagata, Hiromasa

AU - Miller, Adam

AU - Landstreet, Stuart R.

AU - Kuck, Jamie L.

AU - Diamond, Joshua M.

AU - Lederer, David J.

AU - Kawut, Steven M.

AU - Palmer, Scott M.

AU - Wille, Keith M.

AU - Weinacker, Ann

AU - Lama, Vibha N.

AU - Crespo, Maria M.

AU - Orens, Jonathan B.

AU - Shah, Pali D.

AU - Hage, Chadi

AU - Cantu, Edward

AU - Porteous, Mary K.

AU - Dhillon, Gundeep

AU - McDyer, John

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AU - Christie, Jason D.

AU - Ware, Lorraine B.

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N2 - 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.

AB - 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.

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KW - Pulmonology

KW - Respiration

KW - Transplantation

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