Cell-Free Hemoglobin-mediated Increases in Vascular Permeability. A Novel Mechanism of Primary Graft Dysfunction and a New Therapeutic Target

Ciara M. Shaver, Nancy Wickersham, J. Brennan McNeil, Hiromasa Nagata, Gillian Sills, Jamie L. Kuck, David R. Janz, Julie A. Bastarache, Lorraine B. Ware

研究成果: Article

2 引用 (Scopus)

抄録

RATIONALE: Cell-free hemoglobin (CFH) is a potent oxidant associated with poor clinical outcomes in a variety of clinical settings. Recent studies suggest that acetaminophen (APAP), a specific hemoprotein reductant, can abrogate CFH-mediated oxidative injury and organ dysfunction. Preoperative plasma CFH levels are independently associated with primary graft dysfunction (PGD) after lung transplant ( 1 ).

OBJECTIVES: Our objectives were to determine whether CFH would increase lung vascular permeability in the isolated perfused human lung and whether APAP would limit these effects.

METHODS: Human lungs declined for transplant were inflated and perfused with Dulbecco's modified Eagle medium/5% albumin at a pulmonary artery pressure of 8-12 mm Hg. After steady state was achieved, CFH (100 mg/dl) was added to the perfusate ± APAP (15 μg/ml). Lung permeability was measured by continuous monitoring of lung weight gain and by extravasation of Evans blue dye-labeled albumin from the vasculature into bronchoalveolar lavage. To test the mechanism of increased permeability, human pulmonary microvascular endothelial cells were exposed to CFH (0.5 mg/ml) ± APAP (160 μM) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing.

MEASUREMENT AND MAIN RESULTS: In the isolated perfused human lung, CFH increased lung permeability over 2 hours compared with control lungs (12% vs. 2% weight gain from baseline, P = 0.03). Increased vascular permeability was confirmed by a 4.8-fold increase in Evans blue dye-labeled albumin in the airspace compared with control lungs. Pretreatment with APAP prevented lung weight gain (P = 0.06 vs. CFH). In human pulmonary microvascular endothelial cells, CFH increased monolayer permeability (P = 0.03 vs. control), and this was attenuated by APAP (P = 0.045 vs. CFH).

CONCLUSIONS: Circulating CFH increases vascular permeability in the isolated perfused human lung and paracellular permeability in lung microvascular endothelial cells. These effects may explain the association of plasma CFH levels with PGD. The hemoprotein reductant APAP attenuates the effects of CFH and merits further exploration as a potential therapy for PGD prevention.

元の言語English
ページ(範囲)S251-S252
ジャーナルAnnals of the American Thoracic Society
14
発行部数3
DOI
出版物ステータスPublished - 2017 9 1
外部発表Yes

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Primary Graft Dysfunction
Capillary Permeability
Hemoglobins
Lung
Acetaminophen
Permeability
Therapeutics
Weight Gain
Albumins
Evans Blue
Endothelial Cells
Reducing Agents
Plasma Cells
Coloring Agents
Transplants
Eagles

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

これを引用

Cell-Free Hemoglobin-mediated Increases in Vascular Permeability. A Novel Mechanism of Primary Graft Dysfunction and a New Therapeutic Target. / Shaver, Ciara M.; Wickersham, Nancy; McNeil, J. Brennan; Nagata, Hiromasa; Sills, Gillian; Kuck, Jamie L.; Janz, David R.; Bastarache, Julie A.; Ware, Lorraine B.

:: Annals of the American Thoracic Society, 巻 14, 番号 3, 01.09.2017, p. S251-S252.

研究成果: Article

Shaver, Ciara M. ; Wickersham, Nancy ; McNeil, J. Brennan ; Nagata, Hiromasa ; Sills, Gillian ; Kuck, Jamie L. ; Janz, David R. ; Bastarache, Julie A. ; Ware, Lorraine B. / Cell-Free Hemoglobin-mediated Increases in Vascular Permeability. A Novel Mechanism of Primary Graft Dysfunction and a New Therapeutic Target. :: Annals of the American Thoracic Society. 2017 ; 巻 14, 番号 3. pp. S251-S252.
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abstract = "RATIONALE: Cell-free hemoglobin (CFH) is a potent oxidant associated with poor clinical outcomes in a variety of clinical settings. Recent studies suggest that acetaminophen (APAP), a specific hemoprotein reductant, can abrogate CFH-mediated oxidative injury and organ dysfunction. Preoperative plasma CFH levels are independently associated with primary graft dysfunction (PGD) after lung transplant ( 1 ).OBJECTIVES: Our objectives were to determine whether CFH would increase lung vascular permeability in the isolated perfused human lung and whether APAP would limit these effects.METHODS: Human lungs declined for transplant were inflated and perfused with Dulbecco's modified Eagle medium/5{\%} albumin at a pulmonary artery pressure of 8-12 mm Hg. After steady state was achieved, CFH (100 mg/dl) was added to the perfusate ± APAP (15 μg/ml). Lung permeability was measured by continuous monitoring of lung weight gain and by extravasation of Evans blue dye-labeled albumin from the vasculature into bronchoalveolar lavage. To test the mechanism of increased permeability, human pulmonary microvascular endothelial cells were exposed to CFH (0.5 mg/ml) ± APAP (160 μM) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing.MEASUREMENT AND MAIN RESULTS: In the isolated perfused human lung, CFH increased lung permeability over 2 hours compared with control lungs (12{\%} vs. 2{\%} weight gain from baseline, P = 0.03). Increased vascular permeability was confirmed by a 4.8-fold increase in Evans blue dye-labeled albumin in the airspace compared with control lungs. Pretreatment with APAP prevented lung weight gain (P = 0.06 vs. CFH). In human pulmonary microvascular endothelial cells, CFH increased monolayer permeability (P = 0.03 vs. control), and this was attenuated by APAP (P = 0.045 vs. CFH).CONCLUSIONS: Circulating CFH increases vascular permeability in the isolated perfused human lung and paracellular permeability in lung microvascular endothelial cells. These effects may explain the association of plasma CFH levels with PGD. The hemoprotein reductant APAP attenuates the effects of CFH and merits further exploration as a potential therapy for PGD prevention.",
author = "Shaver, {Ciara M.} and Nancy Wickersham and McNeil, {J. Brennan} and Hiromasa Nagata and Gillian Sills and Kuck, {Jamie L.} and Janz, {David R.} and Bastarache, {Julie A.} and Ware, {Lorraine B.}",
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AU - Shaver, Ciara M.

AU - Wickersham, Nancy

AU - McNeil, J. Brennan

AU - Nagata, Hiromasa

AU - Sills, Gillian

AU - Kuck, Jamie L.

AU - Janz, David R.

AU - Bastarache, Julie A.

AU - Ware, Lorraine B.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - RATIONALE: Cell-free hemoglobin (CFH) is a potent oxidant associated with poor clinical outcomes in a variety of clinical settings. Recent studies suggest that acetaminophen (APAP), a specific hemoprotein reductant, can abrogate CFH-mediated oxidative injury and organ dysfunction. Preoperative plasma CFH levels are independently associated with primary graft dysfunction (PGD) after lung transplant ( 1 ).OBJECTIVES: Our objectives were to determine whether CFH would increase lung vascular permeability in the isolated perfused human lung and whether APAP would limit these effects.METHODS: Human lungs declined for transplant were inflated and perfused with Dulbecco's modified Eagle medium/5% albumin at a pulmonary artery pressure of 8-12 mm Hg. After steady state was achieved, CFH (100 mg/dl) was added to the perfusate ± APAP (15 μg/ml). Lung permeability was measured by continuous monitoring of lung weight gain and by extravasation of Evans blue dye-labeled albumin from the vasculature into bronchoalveolar lavage. To test the mechanism of increased permeability, human pulmonary microvascular endothelial cells were exposed to CFH (0.5 mg/ml) ± APAP (160 μM) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing.MEASUREMENT AND MAIN RESULTS: In the isolated perfused human lung, CFH increased lung permeability over 2 hours compared with control lungs (12% vs. 2% weight gain from baseline, P = 0.03). Increased vascular permeability was confirmed by a 4.8-fold increase in Evans blue dye-labeled albumin in the airspace compared with control lungs. Pretreatment with APAP prevented lung weight gain (P = 0.06 vs. CFH). In human pulmonary microvascular endothelial cells, CFH increased monolayer permeability (P = 0.03 vs. control), and this was attenuated by APAP (P = 0.045 vs. CFH).CONCLUSIONS: Circulating CFH increases vascular permeability in the isolated perfused human lung and paracellular permeability in lung microvascular endothelial cells. These effects may explain the association of plasma CFH levels with PGD. The hemoprotein reductant APAP attenuates the effects of CFH and merits further exploration as a potential therapy for PGD prevention.

AB - RATIONALE: Cell-free hemoglobin (CFH) is a potent oxidant associated with poor clinical outcomes in a variety of clinical settings. Recent studies suggest that acetaminophen (APAP), a specific hemoprotein reductant, can abrogate CFH-mediated oxidative injury and organ dysfunction. Preoperative plasma CFH levels are independently associated with primary graft dysfunction (PGD) after lung transplant ( 1 ).OBJECTIVES: Our objectives were to determine whether CFH would increase lung vascular permeability in the isolated perfused human lung and whether APAP would limit these effects.METHODS: Human lungs declined for transplant were inflated and perfused with Dulbecco's modified Eagle medium/5% albumin at a pulmonary artery pressure of 8-12 mm Hg. After steady state was achieved, CFH (100 mg/dl) was added to the perfusate ± APAP (15 μg/ml). Lung permeability was measured by continuous monitoring of lung weight gain and by extravasation of Evans blue dye-labeled albumin from the vasculature into bronchoalveolar lavage. To test the mechanism of increased permeability, human pulmonary microvascular endothelial cells were exposed to CFH (0.5 mg/ml) ± APAP (160 μM) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing.MEASUREMENT AND MAIN RESULTS: In the isolated perfused human lung, CFH increased lung permeability over 2 hours compared with control lungs (12% vs. 2% weight gain from baseline, P = 0.03). Increased vascular permeability was confirmed by a 4.8-fold increase in Evans blue dye-labeled albumin in the airspace compared with control lungs. Pretreatment with APAP prevented lung weight gain (P = 0.06 vs. CFH). In human pulmonary microvascular endothelial cells, CFH increased monolayer permeability (P = 0.03 vs. control), and this was attenuated by APAP (P = 0.045 vs. CFH).CONCLUSIONS: Circulating CFH increases vascular permeability in the isolated perfused human lung and paracellular permeability in lung microvascular endothelial cells. These effects may explain the association of plasma CFH levels with PGD. The hemoprotein reductant APAP attenuates the effects of CFH and merits further exploration as a potential therapy for PGD prevention.

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