Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury.
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ABSTRACT:
SUBMITTER: Shaver CM
PROVIDER: S-EPMC5821179 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:We aimed to identify combinations of biomarkers to enhance the definition of primary graft dysfunction (PGD) for translational research. METHODS:Biomarkers reflecting lung epithelial injury (soluble receptor for advance glycation end products [sRAGE] and surfactant protein-D [SP-D]), coagulation cascade (plasminogen activator inhibitor-1 [PAI-1] and protein C), and cell adhesion (intracellular adhesion molecule-1 [ICAM-1]) were measured in the plasma of 315 individuals derived from the Lung Transplant Outcomes Group cohort at 6 and 24 hours after transplantation. We assessed biomarker utility in 2 ways: first, we tested the discrimination of grade 3 PGD within 72 hours; second, we tested the predictive utility of plasma biomarkers for 90-day mortality. RESULTS:PGD developed in 86 of 315 individuals (27%). Twenty-patients (8%) died within 90 days of transplantation, of which 16 (70%) had PGD. Biomarkers measured at 24 hours had greater discrimination than at 6 hours. Individually, sRAGE (area under the curve [AUC], 0.71) and PAI-1 (AUC, 0.73) had the best discrimination of PGD. The combinations of sRAGE with PAI-1 (AUC, 0.75), PAI-1 with ICAM-1 (AUC, 0.75), and PAI-1 with SP-D (AUC, 0.76) had the best discrimination. Combinations of greater than 2 biomarkers did not significantly enhance discrimination of PGD. ICAM-1 with PAI-1 (AUC, 0.72) and ICAM-1 with sRAGE (AUC, 0.72) had the best prediction for 90-day mortality. The addition of ICAM-1, PAI-1, or sRAGE to the concurrent clinical PGD grade significantly improved the prediction of 90-day mortality (p < 0.001 each). CONCLUSIONS:Measurement of the combination of a marker of impaired fibrinolysis with an epithelial injury or cell adhesion marker had the best discrimination for PGD and prediction for early death and may provide an alternative outcome useful in future research.
| S-EPMC3418416 | biostudies-literature
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.
| S-EPMC5711346 | biostudies-literature
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study Matched case-control observational study: 10 primary graft dysfunction cases vs 16 Good outcome cases. One replicate per array.
2008-09-15 | E-GEOD-9102 | biostudies-arrayexpress
Project description:AimsWe examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes-pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates.ResultsLPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst-mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating β-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance.InnovationWe demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating β-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout.ConclusionOur data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage.
| S-EPMC3691927 | biostudies-literature
Project description:Donor-to-recipient lung size matching at lung transplantation (LTx) can be estimated by the predicted total lung capacity (pTLC) ratio (donor pTLC/recipient pTLC). We aimed to determine whether the pTLC ratio is associated with the risk of primary graft dysfunction (PGD) after bilateral LTx (BLT).We calculated the pTLC ratio for 812 adult BLTs from the Lung Transplant Outcomes Group between March 2002 to December 2010. Patients were stratified by pTLC ratio >1.0 ("oversized") and pTLC ratio ?1.0 ("undersized"). PGD was defined as any ISHLT Grade 3 PGD (PGD3) within 72 hours of reperfusion. We analyzed the association between risk factors and PGD using multivariable conditional logistic regression. As transplant diagnoses can influence the size-matching decisions and also modulate the risk for PGD, we performed pre-specified analyses by assessing the impact of lung size mismatch within diagnostic categories.In univariate analyses oversizing was associated with a 39% lower odds of PGD3 (OR 0.61, 95% CI, 0.45-0.85, p = 0.003). In a multivariate model accounting for center-effects and known PGD risks, oversizing remained independently associated with a decreased odds of PGD3 (OR 0.58, 95% CI 0.38 to 0.88, p = 0.01). The risk-adjusted point estimate was similar for the non-COPD diagnosis groups (OR 0.52, 95% CI 0.32 to 0.86, p = 0.01); however, there was no detected association within the COPD group (OR 0.72, 95% CI 0.29 to 1.78, p = 0.5).Oversized allografts are associated with a decreased risk of PGD3 after BLT; this effect appears most apparent in non-COPD patients.
| S-EPMC4329253 | biostudies-literature
Project description:The term primary graft dysfunction (PGD) incorporates a continuum of disease severity from moderate to severe acute lung injury (ALI) within 72 h of lung transplantation. It represents the most significant obstacle to achieving good early post-transplant outcomes, but is also associated with increased incidence of bronchiolitis obliterans syndrome (BOS) subsequently. PGD is characterised histologically by diffuse alveolar damage, but is graded on clinical grounds with a combination of PaO2/FiO2 (P/F) and the presence of radiographic infiltrates, with 0 being absence of disease and 3 being severe PGD. The aetiology is multifactorial but commonly results from severe ischaemia-reperfusion injury (IRI), with tissue-resident macrophages largely responsible for stimulating a secondary 'wave' of neutrophils and lymphocytes that produce severe and widespread tissue damage. Donor history, recipient health and operative factors may all potentially contribute to the likelihood of PGD development. Work that aims to minimise the incidence of PGD in ongoing, with techniques such as ex vivo perfusion of donor lungs showing promise both in research and in clinical studies. This review will summarise the current clinical status of PGD before going on to discuss its pathophysiology, current therapies available and future directions for clinical management of PGD.
| S-EPMC5723840 | biostudies-other
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study
2008-09-15 | GSE9102 | GEO
Project description:Primary graft dysfunction is a severe acute lung injury syndrome after lung transplantation. Long-term outcomes of subjects with primary graft dysfunction have not been studied.We sought to test the relationship of primary graft dysfunction with both short- and long-term mortality using a large registry.We used data collected on 5,262 patients in the United Network for Organ Sharing/International Society of Heart and Lung Transplantation registry between 1994 and 2000. We assessed outcomes in all subjects; to assess potential bias from the effects of early mortality, we also evaluated subjects who survived at least 1 year, using Cox proportional hazards models with time-varying covariates.The overall incidence of primary graft dysfunction was 10.2% (95% confidence intervals [CI], 9.2, 10.9). The incidence did not vary by year over the period of observation (p = 0.22). All-cause mortality at 30 days was 42.1% for primary graft dysfunction versus 6.1% in patients without graft dysfunction (relative risk = 6.95; 95% CI, 5.98, 8.08; p < 0.001); among subjects who died by 30 days, 43.6% had primary graft dysfunction. Among patients surviving at least 1 year, those who had primary graft dysfunction had significantly worse survival over ensuing years (hazard ratio, 1.35; 95% CI, 1.07, 1.70; p = 0.011). Adjustment for clinical variables including bronchiolitis obliterans syndrome did not change this relationship.Primary graft dysfunction contributes to nearly half of the short-term mortality after lung transplantation. Survivors of primary graft dysfunction have increased risk of death extending beyond the first post-transplant year.
| S-EPMC2718464 | biostudies-other
Project description:Rationale: Primary graft dysfunction (PGD) is the leading cause of early morbidity and mortality after lung transplantation, but the immunologic mechanisms are poorly understood. Innate lymphoid cells (ILC) are a heterogeneous family of immune cells regulating pathologic inflammation and beneficial tissue repair. However, whether changes in donor-derived lung ILC populations are associated with PGD development has never been examined.Objectives: To determine whether PGD in chronic obstructive pulmonary disease or interstitial lung disease transplant recipients is associated with alterations in ILC subset composition within the allograft.Methods: We performed a single-center cohort study of lung transplantation patients with surgical biopsies of donor tissue taken before, and immediately after, allograft reperfusion. Donor immune cells from 18 patients were characterized phenotypically by flow cytometry for single-cell resolution of distinct ILC subsets. Changes in the percentage of ILC subsets with reperfusion or PGD (grade 3 within 72 h) were assessed.Measurements and Main Results: Allograft reperfusion resulted in significantly decreased frequencies of natural killer cells and a trend toward reduced ILC populations, regardless of diagnosis (interstitial lung disease or chronic obstructive pulmonary disease). Seven patients developed PGD (38.9%), and PGD development was associated with selective reduction of the ILC2 subset after reperfusion. Conversely, patients without PGD exhibited significantly higher ILC1 frequencies before reperfusion, accompanied by elevated ILC2 frequencies after allograft reperfusion.Conclusions: The composition of donor ILC subsets is altered after allograft reperfusion and is associated with PGD development, suggesting that ILCs may be involved in regulating lung injury in lung transplant recipients.
| S-EPMC6938146 | biostudies-literature
Project description:Over one-third of lung recipients have preexisting antibodies against lung-restricted antigens: collagen (Col) type V and K-?1 tubulin (KAT). Although clinical studies have shown association of these antibodies with primary graft dysfunction (PGD), their biological significance remains unclear. We tested whether preexisting lung-restricted antibodies can mediate PGD and prevent allotolerance. A murine syngeneic (C57BL/6) or allogeneic (C57BL/6 to BALB/c) left lung transplantation model was used. Rabbit polyclonal antibodies were produced against KAT and Col-V and injected pretransplantation. T cell frequency was analyzed using enzyme-linked immunospot, whereas alloantibodies were determined using flow cytometry. Wet:dry ratio, arterial oxygenation, and histology were used to determine PGD. Preexisting Col-V or KAT, but not isotype control, antibodies lead to dose-dependent development of PGD after syngeneic lung transplantation, as evidenced by poor oxygenation and increased wet:dry ratio. Histology confirmed alveolar and capillary edema. The native right lung remained unaffected. Epitope spreading was observed where KAT antibody treatment led to the development of IL-17-producing CD4+ T cells and humoral response against Col-V, or vice versa. In contrast, isotype control antibody failed to induce Col-V- or KAT-specific cellular or humoral immunity. In addition, none of the mice developed immunity against a non-lung antigen, collagen type II. Preexisting lung-restricted antibodies, but not isotype control, prevented development of allotolerance using the MHC-related 1 and cytotoxic T-lymphocyte-associated protein 4-Ig regimen. Lung-restricted antibodies can induce both early and delayed lung graft dysfunction. These antibodies can also cause spreading of lung-restricted immunity and promote alloimmunity. Antibody-directed therapy to treat preexisting lung-restricted antibodies might reduce PGD after lung transplantation.
| S-EPMC5070112 | biostudies-literature