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Primary graft dysfunction: pathophysiology to guide new preventive therapies.

ABSTRACT: Primary graft dysfunction (PGD) is a common complication of lung transplantation characterized by acute pulmonary edema associated with bilateral pulmonary infiltrates and hypoxemia in the first 3 post-operative days. Development of PGD is a predictor of poor short- and long-term outcomes after lung transplantation, but there are currently limited tools to prevent its occurrence. Areas covered: Several potentially modifiable donor, recipient, and operative risk factors for PGD have been identified. In addition, basic and translational studies in animals and ex vivo lung perfusion systems have identified several biomarkers and mechanisms of injury in PGD. In this review, we outline the clinical and genetic risk factors for PGD and summarize experimental data exploring PGD mechanisms, with a focus on strategies to reduce PGD risk and on potential novel molecular targets for PGD prevention. Expert commentary: Because of the clinical importance of PGD, development of new therapies for prevention and treatment is critically important. Improved understanding of the pathophysiology of clinical PGD provides a framework to explore novel agents to prevent or reverse PGD. Ex vivo lung perfusion provides a new opportunity for rapid development of therapeutics that target this devastating complication of lung transplantation.

SUBMITTER: Shaver CM

PROVIDER: S-EPMC5542681 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Primary graft dysfunction: pathophysiology to guide new preventive therapies.

Shaver Ciara M CM Ware Lorraine B LB

Expert review of respiratory medicine 20170120 2

<h4>Introduction</h4>Primary graft dysfunction (PGD) is a common complication of lung transplantation characterized by acute pulmonary edema associated with bilateral pulmonary infiltrates and hypoxemia in the first 3 post-operative days. Development of PGD is a predictor of poor short- and long-term outcomes after lung transplantation, but there are currently limited tools to prevent its occurrence. Areas covered: Several potentially modifiable donor, recipient, and operative risk factors for P ...[more]

PMID: 28074663

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Project description: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 ).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.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 ?g/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 ?M) for 24 hours and permeability was assessed by electrical cell-substrate impedance sensing.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).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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Primary graft dysfunction: pathophysiology to guide new preventive therapies.

Publications

Primary graft dysfunction: pathophysiology to guide new preventive therapies.

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