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

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

doi:10.1172/jci.insight.98546

Cited by 42 publications

(39 citation statements)

References 57 publications

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“…Beyond this, the degree of organ selection should be based on the research question. Quality metrics have included using only lungs with a baseline AFC rate within a certain range (>10%/h, explained below) (28) or only lungs that reach a stable weight within 30-60 minutes after rewarming (29). For most experiments, the right and left lungs may be considered interchangeable.…”

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

“…For most experiments, the right and left lungs may be considered interchangeable. Depending on the hypothesis to be tested, a single lung may serve as its own control (30), 2 lobes of a single lung may serve as intervention and control (7), or the right and left lung may be perfused separately as intervention and control (29). Preparation.…”

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

“…In early experiments, investigators discovered that the addition of fresh whole human blood to the perfusate was required to generate a robust inflammatory response to E. coli endotoxin (21). Subsequent experiments were conducted with (29,31) or without (32) the addition of 100 ml of fresh human blood to the perfusate, depending on the relevance of the inflammatory response to the experimental design. Type-specific blood is not required because the exposure is brief and the majority of circulating leukocytes in the lungs will have been removed in the procurement process.…”

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

“…Ventilation and oxygenation. Studies with the ex vivo-perfused lung preparation can be done with CPAP of 8 or 10 cmH 2 O (7,11,21,28,33), and recruitment maneuvers to 25 cmH 2 O may be added at the start of the experiment (29). Two studies used positive-pressure ventilation (tidal volume 300 ml, respiratory rate 10/min, FiO 2 0.21) (30,32).…”

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

“…Two studies used positive-pressure ventilation (tidal volume 300 ml, respiratory rate 10/min, FiO 2 0.21) (30,32). To date, the majority of studies have been performed with 95% O 2 and 5% CO 2 (11,21,28,31,33), though 3 studies have been performed with room air (FiO 2 of 0.21) (29,30,32).…”

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

See 4 more Smart Citations

The ex vivo human lung: research value for translational science

Ross¹,

Nesseler²,

Lee³

et al. 2019

JCI Insight

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Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

Section: Ex Vivo-perfused Human Lungmentioning

confidence: 99%

See 3 more Smart Citations

The ex vivo human lung: research value for translational science

Ross¹,

Nesseler²,

Lee³

et al. 2019

JCI Insight

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Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis

Ware,

Files,

Fowler

et al. 2024

JAMA

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ImportanceAcetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.ObjectiveTo determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.Design, Setting, and ParticipantsPhase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation.InterventionPatients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days.Main Outcome and MeasuresThe primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL.ResultsOf 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, −1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, −6.3; 95% CI, −10.8 to −1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen.Conclusions and RelevanceIntravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients.Trial RegistrationClinicalTrials.gov Identifier: NCT04291508

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Transpulmonary generation of cell‐free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms

et al. 2023

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Circulating cell‐free hemoglobin (CFH) is elevated in pulmonary arterial hypertension (PAH) and associated with poor outcomes but the mechanisms are unknown. We hypothesized that CFH is generated from the pulmonary circulation and inadequately cleared in PAH. Transpulmonary CFH (difference between wedge and pulmonary artery positions) and lung hemoglobin α were analyzed in patients with PAH and healthy controls. Haptoglobin genotype and plasma hemoglobin processing proteins were analyzed in patients with PAH, unaffected bone morphogenetic protein receptor type II mutation carriers (UMCs), and control subjects. Transpulmonary CFH was increased in patients with PAH ( p = 0.04) and correlated with pulmonary vascular resistanc (PVR) ( r s = 0.75, p = 0.02) and mean pulmonary arterial pressure (mPAP) ( r s = 0.78, p = 0.02). Pulmonary vascular hemoglobin α protein was increased in patients with PAH ( p = 0.006), especially in occluded vessels ( p = 0.04). Haptoglobin genotype did not differ between groups. Plasma haptoglobin was higher in UMCs compared with both control subjects ( p = 0.03) and patients with HPAH ( p < 0.0001); patients with IPAH had higher circulating haptoglobin levels than patients with HPAH ( p = 0.006). Notably, circulating CFH to haptoglobin ratio was elevated in patients with HPAH compared to control subjects ( p = 0.02) and UMCs ( p = 0.006). Moreover, in patients with PAH, CFH: haptoglobin correlated with PVR ( r s = 0.37, p = 0.0004) and mPAP ( r s = 0.25, p = 0.02). Broad alterations in other plasma hemoglobin processing proteins (hemopexin, heme oxygenase‐1, and sCD163) were observed. In conclusion, pulmonary vascular CFH is associated with increased PVR and mPAP in PAH and dysregulated CFH clearance may contribute to PAH pathology. Further study is needed to determine whether targeting CFH is a viable therapeutic for pulmonary vascular dysfunction in PAH.

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

Cited by 42 publications

References 57 publications

The ex vivo human lung: research value for translational science

The ex vivo human lung: research value for translational science

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis

Transpulmonary generation of cell‐free hemoglobin contributes to vascular dysfunction in pulmonary arterial hypertension via dysregulated clearance mechanisms

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