Publications by authors named "Victor E Laubach"

98 Publications

Endothelial Transient Receptor Potential V4 Channels Mediate Lung Ischemia-Reperfusion Injury.

Ann Thorac Surg 2021 May 4. Epub 2021 May 4.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA. Electronic address:

Background: Lung ischemia-reperfusion injury (IRI), involving severe inflammation and edema, is a major cause of primary graft dysfunction following transplant. Activation of transient receptor potential vanilloid 4 (TRPV4) channels modulates vascular permeability. Thus, this study tests the hypothesis that endothelial TRPV4 channels mediate lung IRI.

Methods: C57BL/6 wild-type (WT), TRPV4, tamoxifen-inducible endothelial TRPV4 knockout (TRPV4), and tamoxifen-treated control (TRPV4) mice underwent lung IR using a left lung hilar-ligation model (n≥6 mice/group). WT mice were also treated with a TRPV4-specific inhibitor (GSK2193874; 1mg/kg) (WT+GSK219). Partial pressure of oxygen (PaO), edema (wet-to-dry weight ratio), compliance, neutrophil infiltration, and cytokine concentrations in bronchioalveolar lavage fluid were assessed. Pulmonary microvascular endothelial cells (PMVECs) were characterized in vitro following exposure to hypoxia-reoxygenation.

Results: Compared to WT, PaO following IR was significantly improved in TRPV4 mice (133.1±43.9 vs 427.8±83.1 mmHg, p<0.001) and WT+GSK219 mice (133.1±43.9 vs 447.0±67.6 mmHg, p<0.001). Pulmonary edema and neutrophil infiltration were also significantly reduced after IR in TRPV4 and WT+GSK219 mice versus WT. TRPV4 mice following IR demonstrated significantly improved oxygenation versus control (109.2±21.6 vs 405.3±41.4 mmHg, p<0.001) as well as significantly improved compliance, and significantly less edema, neutrophil infiltration and proinflammatory cytokine production (TNF-α, CXCL1, IL-17, IFN-γ). Hypoxia-reoxygenation-induced permeability and CXCL1 expression by PMVECs was significantly attenuated by TRPV4 inhibitors.

Conclusions: Endothelial TRPV4 plays a key role in vascular permeability and lung inflammation following IR. TRPV4 channels may be a promising therapeutic target to mitigate lung IRI and decrease the incidence of primary graft dysfunction following transplant. (Word Count: 249/250).
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.052DOI Listing
May 2021

Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension.

Proc Natl Acad Sci U S A 2021 Apr;118(17)

Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908;

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1-TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1-TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.
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http://dx.doi.org/10.1073/pnas.2023130118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092599PMC
April 2021

Secondary Burn Progression Mitigated by an Adenosine 2A Receptor Agonist.

J Burn Care Res 2021 Mar 26. Epub 2021 Mar 26.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.

Background: Current burn therapy is largely supportive with limited therapies to curb secondary burn progression. Adenosine 2A receptor (A2AR) agonists have anti-inflammatory effects with decreased inflammatory cell infiltrate and release of pro-inflammatory mediators. Using a porcine comb burn model, we examined whether A2AR agonists could mitigate burn progression.

Study Design: Eight full-thickness comb burns (4 prongs with 3 spaces per comb) per pig were generated with the following specifications: temperature 115° C, 3 kg force, and 30 second application time. In a randomized fashion, animals (4 per group) were then treated with A2AR agonist (ATL-1223, 3 ng/kg/min, intravenous infusion over 6 hours) or vehicle control. Necrotic interspace development was the primary outcome and additional histologic assessments were conducted.

Results: Analysis of unburned interspaces (72 per group) revealed that ATL-1223 treatment decreased the rate of necrotic interspace development over the first 4 days following injury (p<0.05). Treatment significantly decreased dermal neutrophil infiltration at 48 hours following burn (14.63±4.30 vs 29.71±10.76 neutrophils/high-power field, p=0.029). Additionally, ATL-1223 treatment was associated with fewer interspaces with evidence of microvascular thrombi through post-burn day 4 (18.8% vs 56.3%, p=0.002). Two weeks following insult, the depth of injury at distinct burn sites (adjacent to interspaces) was significantly reduced by ATL-1223 treatment (2.91±0.47 vs 3.28±0.58 mm, p=0.038).

Conclusion: This work demonstrates the ability of an A2AR agonist to mitigate burn progression through dampening local inflammatory processes. Extended dosing strategies may yield additional benefit and improve cosmetic outcome in those with severe injury.
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http://dx.doi.org/10.1093/jbcr/irab053DOI Listing
March 2021

Two Hours of In Vivo Lung Perfusion Improves Lung Function in Sepsis-Induced Acute Respiratory Distress Syndrome.

Semin Thorac Cardiovasc Surg 2021 Mar 11. Epub 2021 Mar 11.

Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Sepsis is the leading cause of acute respiratory distress syndrome (ARDS) in adults and carries a high mortality. Utilizing a previously validated porcine model of sepsis-induced ARDS, we sought to refine our novel therapeutic technique of in vivo lung perfusion (IVLP). We hypothesized that 2 hours of IVLP would provide non-inferior lung rehabilitation compared to 4 hours of treatment. Adult swine (n = 8) received lipopolysaccharide to develop ARDS and were placed on central venoarterial extracorporeal membrane oxygenation. Animals were randomized to 2 vs 4 hours of IVLP. The left pulmonary vessels were cannulated to IVLP using antegrade Steen solution. After IVLP treatment, the left lung was decannulated and reperfused for 4 hours. Total lung compliance and pulmonary venous gases from the right lung (control) and left lung (treatment) were sampled hourly. Biochemical analysis of tissue and bronchioalveolar lavage was performed along with tissue histologic assessment. Throughout IVLP and reperfusion, treated left lung PaO/FiO ratio was significantly higher than the right lung control in the 2-hour group (332.2 ± 58.9 vs 264.4 ± 46.5, P = 0.01). In the 4-hour group, there was no difference between treatment and control lung PaO/FiO ratio (258.5 ± 72.4 vs 253.2 ± 90.3, P = 0.58). Wet-to-dry weight ratios demonstrated reduced edema in the treated left lungs of the 2-hour group (6.23 ± 0.73 vs 7.28 ± 0.61, P = 0.03). Total lung compliance was also significantly improved in the 2-hour group. Two hours of IVLP demonstrated superior lung function in this preclinical model of sepsis-induced ARDS. Clinical translation of IVLP may shorten duration of mechanical support and improve outcomes.
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http://dx.doi.org/10.1053/j.semtcvs.2021.02.034DOI Listing
March 2021

Role of the purinergic signaling network in lung ischemia-reperfusion injury.

Curr Opin Organ Transplant 2021 Apr;26(2):250-257

Department of Surgery.

Purpose Of Review: Primary graft dysfunction (PGD) is the leading cause of early mortality following lung transplantation and is typically caused by lung ischemia-reperfusion injury (IRI). Current management of PGD is largely supportive and there are no approved therapies to prevent lung IRI after transplantation. The purinergic signaling network plays an important role in this sterile inflammatory process, and pharmacologic manipulation of said network is a promising therapeutic strategy. This review will summarize recent findings in this area.

Recent Findings: In the past 18 months, our understanding of lung IRI has improved, and it is becoming clear that the purinergic signaling network plays a vital role. Recent works have identified critical components of the purinergic signaling network (Pannexin-1 channels, ectonucleotidases, purinergic P1 and P2 receptors) involved in inflammation in a number of pathologic states including lung IRI. In addition, a functionally-related calcium channel, the transient receptor potential vanilloid type 4 (TRPV4) channel, has recently been linked to purinergic signaling and has also been shown to mediate lung IRI.

Summary: Agents targeting components of the purinergic signaling network are promising potential therapeutics to limit inflammation associated with lung IRI and thus decrease the risk of developing PGD.
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http://dx.doi.org/10.1097/MOT.0000000000000854DOI Listing
April 2021

Isolated Lung Perfusion in the Management of Acute Respiratory Distress Syndrome.

Int J Mol Sci 2020 Sep 17;21(18). Epub 2020 Sep 17.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22902, USA.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. While our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. There is a dramatic need for the development and breakthrough of new methods for the treatment of ARDS. Isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. Initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ARDS. This review presents current tenants of ARDS management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (EVLP) has paved the way for current investigations utilizing in vivo lung perfusion (IVLP) in the treatment of severe ARDS.
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http://dx.doi.org/10.3390/ijms21186820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555278PMC
September 2020

Consideration of Pannexin 1 channels in COVID-19 pathology and treatment.

Am J Physiol Lung Cell Mol Physiol 2020 07 10;319(1):L121-L125. Epub 2020 Jun 10.

Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia.

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http://dx.doi.org/10.1152/ajplung.00146.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347959PMC
July 2020

SPECT imaging of lung ischemia-reperfusion injury using [Tc]cFLFLF for molecular targeting of formyl peptide receptor 1.

Am J Physiol Lung Cell Mol Physiol 2020 02 4;318(2):L304-L313. Epub 2019 Dec 4.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.

Primary graft dysfunction after lung transplantation, a consequence of ischemia-reperfusion injury (IRI), is a major cause of morbidity and mortality. IRI involves acute inflammation and innate immune cell activation, leading to rapid infiltration of neutrophils. Formyl peptide receptor 1 (FPR1) expressed by phagocytic leukocytes plays an important role in neutrophil function. The cell surface expression of FPR1 is rapidly and robustly upregulated on neutrophils in response to inflammatory stimuli. Thus, we hypothesized that use of [Tc]cFLFLF, a selective FPR1 peptide ligand, would permit in vivo neutrophil labeling and noninvasive imaging of IRI using single-photon emission computed tomography (SPECT). A murine model of left lung IRI was utilized. Lung function, neutrophil infiltration, and SPECT imaging were assessed after 1 h of ischemia and 2, 12, or 24 h of reperfusion. [Tc]cFLFLF was injected 2 h before SPECT. Signal intensity by SPECT and total probe uptake by gamma counts were 3.9- and 2.3-fold higher, respectively, in left lungs after ischemia and 2 h of reperfusion versus sham. These values significantly decreased with longer reperfusion times, correlating with resolution of IRI as shown by improved lung function and decreased neutrophil infiltration. SPECT results were confirmed using Cy7-cFLFLF-based fluorescence imaging of lungs. Immunofluorescence microscopy confirmed cFLFLF binding primarily to activated neutrophils. These results demonstrate that [Tc]cFLFLF SPECT enables noninvasive detection of lung IRI and permits monitoring of resolution of injury over time. Clinical application of [Tc]cFLFLF SPECT may permit diagnosis of lung IRI for timely intervention to improve outcomes after transplantation.
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http://dx.doi.org/10.1152/ajplung.00220.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052676PMC
February 2020

Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death.

J Heart Lung Transplant 2020 01 18;39(1):74-82. Epub 2019 Sep 18.

Departments of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Background: Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs.

Methods: A porcine DCD and EVLP model was utilized. Two groups (n = 4 per group) of DCD lungs were randomized to target EVLP flows of 40% (high-flow) or 20% (low-flow) predicted cardiac output based on 100 ml/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion.

Results: After transplant, left lung-specific pulmonary vein partial pressure of oxygen was significantly higher in the low-flow group at 3 and 4 hours of reperfusion (3-hour: 496.0 ± 87.7 mm Hg vs. 252.7 ± 166.0 mm Hg, p = 0.017; 4-hour: 429.7 ± 93.6 mm Hg vs. 231.5 ± 178 mm Hg, p = 0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8 ± 9.4 ml/cm HO vs. 10.2 ± 3.5 ml/cm HO, p = 0.022) and throughout all subsequent time points in the low-flow group. After reperfusion, lung wet-to-dry weight ratio (7.1 ± 0.7 vs. 8.8 ± 1.1, p = 0.040) and interleukin-1β expression (927 ± 300 pg/ng protein vs. 2,070 ± 874 pg/ng protein, p = 0.048) were significantly reduced in the low-flow group.

Conclusions: EVLP of DCD lungs with low-flow targets of 20% predicted cardiac output improves lung function, reduces edema, and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.
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http://dx.doi.org/10.1016/j.healun.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001159PMC
January 2020

Extracellular nucleotide signaling in solid organ transplantation.

Am J Transplant 2020 03 4;20(3):633-640. Epub 2019 Nov 4.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.

The role of extracellular purine nucleotides, including adenosine triphosphate (ATP) and adenosine, as modulators of posttransplantation outcome and ischemia-reperfusion injury is becoming increasingly evident. Upon pathological release of ATP, binding and activation of P2 purinergic surface receptors promote tissue injury and inflammation, while the expression and activation of P1 receptors for adenosine have been shown to attenuate inflammation and limit ischemia-induced damage, which are central to the viability and long-term success of allografts. Here we review the current state of the transplant field with respect to the role of extracellular nucleotide signaling, with a focus on the sources and functions of extracellular ATP. The connection between ischemia reperfusion, purinergic signaling, and graft preservation, as well as the role of ATP and adenosine as driving factors in the promotion and suppression of posttransplant inflammation and allograft rejection, are discussed. We also examine novel therapeutic approaches that take advantage of the ischemia-reperfusion-responsive and immunomodulatory roles for purinergic signaling with the goal of enhancing graft viability, attenuating posttransplant inflammation, and minimizing complications including rejection, graft failure, and associated comorbidities.
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http://dx.doi.org/10.1111/ajt.15651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042041PMC
March 2020

Novel Regulators and Targets of Redox Signaling in Pulmonary Vasculature.

Curr Opin Physiol 2019 Jun 9;9:87-93. Epub 2019 May 9.

Robert M. Berne Cardiovascular Research Center, University of Virginia-School of Medicine, Charlottesville, VA, 22908, USA.

Dysregulated redox signaling in pulmonary vasculature is central to the development of pulmonary arterial hypertension (PAH) and lung injury. Modulators of reactive oxygen species (ROS) production and downstream signaling targets are critical for mediating the physiological or pathological effects of ROS. Understanding the complex interactions between the modulators and signaling targets of ROS is essential for developing novel strategies to prevent or attenuate lung pathologies. In this review, we discuss recent studies on the modulators and targets of ROS in pulmonary endothelial and smooth muscle cells, their cellular effects, and the disease conditions associated with dysregulated redox signaling.
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http://dx.doi.org/10.1016/j.cophys.2019.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690609PMC
June 2019

Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation.

Ann Surg 2019 06;269(6):1176-1183

Department of Surgery, University of Virginia, Charlottesville, VA.

Objective: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR.

Summary Background Data: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist.

Methods: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups.

Results: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups.

Conclusions: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.
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http://dx.doi.org/10.1097/SLA.0000000000002685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757347PMC
June 2019

Role of medical and molecular imaging in COPD.

Clin Transl Med 2019 Apr 15;8(1):12. Epub 2019 Apr 15.

Department of Biomedical Engineering, University of Virginia School of Medicine, P.O. Box 800759, Charlottesville, VA, 22908, USA.

Chronic obstructive pulmonary disease (COPD) is expected to climb on the podium of the leading causes of mortality worldwide in the upcoming decade. Clinical diagnosis of COPD has classically relied upon detecting irreversible airflow obstruction on pulmonary function testing as a global assessment of pulmonary physiology. However, the outcome is still not favorable to decrease mortality due to COPD. Progress made in both medical and molecular imaging fields are beginning to offer additional tools to address this clinical problem. This review aims to describe medical and molecular imaging modalities used to diagnose COPD and to select patients for appropriate treatments and to monitor response to therapy.
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http://dx.doi.org/10.1186/s40169-019-0231-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465368PMC
April 2019

Can Lung Transplant Surgeons Still Be Scientists? High Productivity Despite Competitive Funding.

Heart Surg Forum 2019 01 8;22(1):E001-E007. Epub 2019 Jan 8.

Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.

Background: Today's declining federal budget for scientific research is making it consistently more difficult to become federally funded. We hypothesized that even in this difficult era, surgeon-scientists have remained among the most productive and impactful researchers in lung transplantation.

Methods: Grants awarded by the NIH for the study of lung transplantation between 1985 and 2015 were identified by searching NIH RePORTER for 5 lung transplantation research areas. A grant impact metric was calculated for each grant by dividing the sum of impact factors for all associated manuscripts by the total funding for that grant. We used nonparametric univariate analysis to compare grant impact metrics by department.

Results: We identified 109 lung transplantation grants, totaling approximately $300 million, resulting in 2304 papers published in 421 different journals. Surgery has the third highest median grant impact metric (4.2 per $100,000). The department of surgery had a higher median grant impact metric compared to private companies (P <.0001). There was no statistical difference in the grant impact metric compared to all other medical specialties, individual departments with multiple grants, or all basic science departments (all P >.05).

Conclusions: Surgeon-scientists in the field of lung transplantation have received fewer grants and less total funding compared to other researchers but have maintained an equally high level of productivity and impact. The dual-threat academic surgeon-scientist is an important asset to the research community and should continue to be supported by the NIH.
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http://dx.doi.org/10.1532/hsf.2024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468987PMC
January 2019

Ex Vivo Assessment of Porcine Donation After Circulatory Death Lungs That Undergo Increasing Warm Ischemia Times.

Transplant Direct 2018 Dec 12;4(12):e405. Epub 2018 Nov 12.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA.

Background: Increased utilization of donation after circulatory death (DCD) lungs may help alleviate the supply/demand mismatch between available donor organs and lung transplant candidates. Using an established porcine DCD model, we sought to determine the effect of increasing warm ischemia time (WIT) after circulatory arrest on lung function during ex vivo lung perfusion (EVLP).

Methods: Porcine donors (n = 15) underwent hypoxic cardiac arrest, followed by 60, 90, or 120 minutes of WIT before procurement and 4 hours of normothermic EVLP. Oxygenation, pulmonary artery pressure, airway pressure, and compliance were measured hourly. Lung injury scores were assessed histologically after 4 hours of EVLP.

Results: After EVLP, all 3 groups met all the criteria for transplantation, except for 90-minute WIT lungs, which had a mean pulmonary artery pressure increase greater than 15%. There were no significant differences between groups as assessed by final oxygenation capacity, as well as changes in pulmonary artery pressure, airway pressure, or lung compliance. Histologic lung injury scores as well as lung wet-to-dry weight ratios did not significantly differ between groups.

Conclusions: These results suggest that longer WIT alone (up to 120 minutes) does not predict worse lung function at the conclusion of EVLP. Expanding acceptable WIT after circulatory death may eventually allow for increased utilization of DCD lungs in procurement protocols.
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http://dx.doi.org/10.1097/TXD.0000000000000845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283086PMC
December 2018

Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury.

Am J Physiol Lung Cell Mol Physiol 2018 08 10;315(2):L301-L312. Epub 2018 May 10.

Department of Surgery, University of Virginia School of Medicine , Charlottesville, Virginia.

Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is a key mediator of vascular inflammation and edema after I/R and that IRI can be blocked by Panx1 antagonism. A murine hilar ligation model of IRI was used whereby left lungs underwent 1 h of ischemia and 2 h of reperfusion. Treatment of wild-type mice with Panx1 inhibitors (carbenoxolone or probenecid) significantly attenuated I/R-induced pulmonary dysfunction, edema, cytokine production, and neutrophil infiltration versus vehicle-treated mice. In addition, VE-Cad-Cre/Panx1 mice (tamoxifen-inducible deletion of Panx1 in vascular endothelium) treated with tamoxifen were significantly protected from IRI (reduced dysfunction, endothelial permeability, edema, proinflammatory cytokines, and neutrophil infiltration) versus vehicle-treated mice. Furthermore, extracellular ATP levels in bronchoalveolar lavage fluid is Panx1-mediated after I/R as it was markedly attenuated by Panx1 antagonism in wild-type mice and by endothelial-specific Panx1 deficiency. Panx1 gene expression in lungs after I/R was also significantly elevated compared with sham. In vitro experiments demonstrated that TNF-α and/or hypoxia-reoxygenation induced ATP release from lung microvascular endothelial cells, which was attenuated by Panx1 inhibitors. This study is the first, to our knowledge, to demonstrate that endothelial Panx1 plays a key role in mediating vascular permeability, inflammation, edema, leukocyte infiltration, and lung dysfunction after I/R. Pharmacological antagonism of Panx1 activity may be a novel therapeutic strategy to prevent IRI and primary graft dysfunction after lung transplantation.
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http://dx.doi.org/10.1152/ajplung.00004.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139659PMC
August 2018

Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion.

J Thorac Cardiovasc Surg 2018 08 11;156(2):910-917. Epub 2018 Mar 11.

Department of Surgery, University of Virginia School of Medicine, Charlottesville, Va. Electronic address:

Background: Sphingosine-1-phosphate regulates endothelial barrier integrity and promotes cell survival and proliferation. We hypothesized that upregulation of sphingosine-1-phosphate during ex vivo lung perfusion would attenuate acute lung injury and improve graft function.

Methods: C57BL/6 mice (n = 4-8/group) were euthanized, followed by 1 hour of warm ischemia and 1 hour of cold preservation in a model of donation after cardiac death. Subsequently, mice underwent 1 hour of ex vivo lung perfusion with 1 of 4 different perfusion solutions: Steen solution (Steen, control arm), Steen with added sphingosine-1-phosphate (Steen + sphingosine-1-phosphate), Steen plus a selective sphingosine kinase 2 inhibitor (Steen + sphingosine kinase inhibitor), or Steen plus both additives (Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor). During ex vivo lung perfusion, lung compliance and pulmonary artery pressure were continuously measured. Pulmonary vascular permeability was assessed with injection of Evans Blue dye.

Results: The combination of 1 hour of warm ischemia, followed by 1 hour of cold ischemia created significant lung injury compared with lungs that were immediately harvested after circulatory death and put on ex vivo lung perfusion. Addition of sphingosine-1-phosphate or sphingosine kinase inhibitor alone did not significantly improve lung function during ex vivo lung perfusion compared with Steen without additives. However, group Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor resulted in significantly increased compliance (110% ± 13.9% vs 57.7% ± 6.6%, P < .0001) and decreased pulmonary vascular permeability (33.1 ± 11.9 μg/g vs 75.8 ± 11.4 μg/g tissue, P = .04) compared with Steen alone.

Conclusions: Targeted drug therapy with a combination of sphingosine-1-phosphate + sphingosine kinase inhibitor during ex vivo lung perfusion improves lung function in a murine donation after cardiac death model. Elevation of circulating sphingosine-1-phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation.
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http://dx.doi.org/10.1016/j.jtcvs.2018.02.090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056006PMC
August 2018

Novel Role of IL (Interleukin)-1β in Neutrophil Extracellular Trap Formation and Abdominal Aortic Aneurysms.

Arterioscler Thromb Vasc Biol 2018 04 22;38(4):843-853. Epub 2018 Feb 22.

From the Department of Surgery (A.K.M., M.S., J.P.D., N.P., V.E.L., G.S., G.A., G.R.U.), Department of Pharmacology (A.K.M., V.S., N.L.), Robert M. Berne Cardiovascular Research Center (A.K.M., N.L., G.A., G.R.U.), Department of Molecular Physiology and Biological Physics (G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville.

Objective: Neutrophils promote experimental abdominal aortic aneurysm (AAA) formation via a mechanism that is independent from MMPs (matrix metalloproteinases). Recently, we reported a dominant role of IL (interleukin)-1β in the formation of murine experimental AAAs. Here, the hypothesis that IL-1β-induced neutrophil extracellular trap formation (NETosis) promotes AAA was tested.

Approach And Results: NETs were identified through colocalized staining of neutrophil, Cit-H3 (citrullinated histone H3), and DNA, using immunohistochemistry. NETs were detected in human AAAs and were colocalized with IL-1β. In vitro, IL-1RA attenuated IL-1β-induced NETosis in human neutrophils. Mechanistically, IL-1β treatment of isolated neutrophils induced nuclear localization of ceramide synthase 6 and synthesis of C16-ceramide, which was inhibited by IL-1RA or fumonisin B1, an inhibitor of ceramide synthesis. Furthermore, IL-1RA or fumonisin B1 attenuated IL1-β-induced NETosis. In an experimental model of murine AAA, NETs were detected at a very early stage-day 3 of aneurysm induction. IL-1β-knockout mice demonstrated significantly lower infiltration of neutrophils to aorta and were protected from AAA. Adoptive transfer of wild-type neutrophils promoted AAA formation in IL-1β-knockout mice. Moreover, treatment of wild-type mice with Cl-amidine, an inhibitor NETosis, significantly attenuated AAA formation, whereas, treatment with deoxyribonuclease, a DNA digesting enzyme, had no effect on AAA formation.

Conclusions: Altogether, the results suggest a dominant role of IL-1β-induced NETosis in AAA formation.
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http://dx.doi.org/10.1161/ATVBAHA.117.309897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864548PMC
April 2018

Expanding the donor lung pool: how many donations after circulatory death organs are we missing?

J Surg Res 2018 03 11;223:58-63. Epub 2017 Nov 11.

Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health System, Charlottesville, Virginia. Electronic address:

Background: The number of patients with end-stage pulmonary disease awaiting lung transplantation is at an all-time high, while the supply of available organs remains stagnant. Utilizing donation after circulatory death (DCD) donors may help to address the supply-demand mismatch. The objective of this study is to determine the potential donor pool expansion with increased procurement of DCD organs from patients who die at hospitals.

Material And Methods: The charts of all patients who died at a single, rural, quaternary-care institution between August 2014 and June 2015 were reviewed for lung transplant candidacy. Inclusion criteria were age <65 y, absence of cancer and lung pathology, and cause of death other than respiratory or sepsis.

Results: A total of 857 patients died within a 1-year period and were stratified by age: pediatric <15 y (n = 32, 4%), young 15-64 y (n = 328, 38%), and old >65 y (n = 497, 58%). Those without cancer totaled 778 (90.8%) and 512 (59%) did not have lung pathology. This leaves 85 patients qualifying for DCD lung donation (pediatric n = 10, young n = 75, and old n = 0). Potential donors were significantly more likely to have clear chest X-rays (24.3% versus 10.0%, P < 0.0001) and higher mean PaO2/FiO2 (342.1 versus 197.9, P < 0.0001) compared with ineligible patients.

Conclusions: A significant number of DCD lungs are available every year from patients who die within hospitals. We estimate the use of suitable DCD lungs could potentially result in a significant increase in the number of lungs available for transplantation.
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http://dx.doi.org/10.1016/j.jss.2017.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475907PMC
March 2018

Molecular imaging of pulmonary diseases.

Respir Res 2018 01 24;19(1):17. Epub 2018 Jan 24.

Department of Surgery, University of Virginia, P.O. Box 801359, Charlottesville, VA, 22908, USA.

Imaging holds an important role in the diagnosis of lung diseases. Along with clinical tests, noninvasive imaging techniques provide complementary and valuable information that enables a complete differential diagnosis. Various novel molecular imaging tools are currently under investigation aimed toward achieving a better understanding of lung disease physiopathology as well as early detection and accurate diagnosis leading to targeted treatment. Recent research on molecular imaging methods that may permit differentiation of the cellular and molecular components of pulmonary disease and monitoring of immune activation are detailed in this review. The application of molecular imaging to lung disease is currently in its early stage, especially compared to other organs or tissues, but future studies will undoubtedly reveal useful pulmonary imaging probes and imaging modalities.
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http://dx.doi.org/10.1186/s12931-018-0716-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784614PMC
January 2018

Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death.

Respir Res 2017 12 21;18(1):212. Epub 2017 Dec 21.

Department of Surgery, University of Virginia, P.O. Box 801359, Charlottesville, VA, 22908, USA.

Background: Lung ischemia-reperfusion (IR) injury after transplantation as well as acute shortage of suitable donor lungs are two critical issues impacting lung transplant patients. This study investigates the anti-inflammatory and immunomodulatory role of human mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) to attenuate lung IR injury and improve of ex-vivo lung perfusion (EVLP)-mediated rehabilitation in donation after circulatory death (DCD) lungs.

Methods: C57BL/6 wild-type (WT) mice underwent sham surgery or lung IR using an in vivo hilar-ligation model with or without MSCs or EVs. In vitro studies used primary iNKT cells and macrophages (MH-S cells) were exposed to hypoxia/reoxygenation with/without co-cultures with MSCs or EVs. Also, separate groups of WT mice underwent euthanasia and 1 h of warm ischemia and stored at 4 °C for 1 h followed by 1 h of normothermic EVLP using Steen solution or Steen solution containing MSCs or EVs.

Results: Lungs from MSCs or EV-treated mice had significant attenuation of lung dysfunction and injury (decreased edema, neutrophil infiltration and myeloperoxidase levels) compared to IR alone. A significant decrease in proinflammatory cytokines (IL-17, TNF-α, CXCL1 and HMGB1) and upregulation of keratinocyte growth factor, prostaglandin E2 and IL-10 occurred in the BAL fluid from MSC or EV-treated mice after IR compared to IR alone. Furthermore, MSCs or EVs significantly downregulated iNKT cell-produced IL-17 and macrophage-produced HMGB1 and TNF-α after hypoxia/reoxygenation. Finally, EVLP of DCD lungs with Steen solution including MSCs or EVs provided significantly enhanced protection versus Steen solution alone. Co-cultures of MSCs or EVs with lung endothelial cells prevents neutrophil transendothelial migration after exposure to hypoxia/reoxygenation and TNF-α/HMGB1 cytomix.

Conclusions: These results suggest that MSC-derived EVs can attenuate lung inflammation and injury after IR as well as enhance EVLP-mediated reconditioning of donor lungs. The therapeutic benefits of EVs are in part mediated through anti-inflammatory promoting mechanisms via attenuation of immune cell activation as well as prevention of endothelial barrier integrity to prevent lung edema. Therefore, MSC-derived EVs offer a potential therapeutic strategy to treat post-transplant IR injury as well as rehabilitation of DCD lungs.
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http://dx.doi.org/10.1186/s12931-017-0704-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740880PMC
December 2017

In vivo lung perfusion rehabilitates sepsis-induced lung injury.

J Thorac Cardiovasc Surg 2018 01 14;155(1):440-448.e2. Epub 2017 Sep 14.

Department of Surgery, University of Virginia, Charlottesville, Va. Electronic address:

Background: Sepsis is the leading cause of lung injury in adults and can lead to acute respiratory distress syndrome (ARDS). Using a novel technique of isolated in vivo lung perfusion (IVLP), we hypothesized that normothermic IVLP will improve oxygenation and compliance in a porcine model of sepsis-induced lung injury.

Methods: Mature adult swine (n = 8) were administered lipopolysaccharide (LPS; 50 μg/kg over 2 hours) via the external jugular vein, followed by sternotomy and central extracorporeal membrane oxygenation (ECMO) cannulation (right atrium to ascending aorta). The left pulmonary artery (inflow) and left superior and inferior pulmonary veins (outflow) were dissected out and cannulated to deliver isolated perfusion to the left lung. After 4 hours of normothermic IVLP with Steen solution, the left lung then underwent 4 hours of reperfusion after IVLP decannulation. Airway pressures and lung-specific pulmonary vein blood gases from the right lung (LPS control) and left lung (LPS + IVLP) of the same animal were compared.

Results: All animals demonstrated a significant reduction in the ratio of partial pressure of oxygen in arterial blood (PaO)/fraction of inspired oxygen (FiO) (P/F ratio) and total lung compliance at 2 hours after the start of LPS infusion (mean, 469 ± 19.7 mm Hg vs 222.2 ± 21.4 mm Hg; P < .0001). After reperfusion, 6 animals (75%) exhibited improved lung function, allowing for ECMO decannulation. Lung-specific oxygenation was superior in the left lung after 4 hours of reperfusion (mean, 310.5 ± 54.7 mm Hg vs 201.1 ± 21.7 mm Hg; P = .01). Similarly, total lung compliance improved after IVLP of the left lung. The lung wet weight to dry weight ratio demonstrated reduced edema in rehabilitated left lungs (mean, 6.5 ± 0.3 vs 7.5 ± 0.4; P = .04).

Conclusions: IVLP successfully rehabilitated LPS-injured lungs compared to ECMO support alone in this preclinical porcine model.
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http://dx.doi.org/10.1016/j.jtcvs.2017.08.124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744259PMC
January 2018

Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice.

Free Radic Biol Med 2017 12 2;113:212-223. Epub 2017 Oct 2.

Center for Skeletal Muscle Research at Robert Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA; Departments of Medicine, University of Virginia, Charlottesville, VA 22908, USA; Departments of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Departments of Molecular Physiology & Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

Multiple organ dysfunction syndrome (MODS) is a detrimental clinical complication in critically ill patients with high mortality. Emerging evidence suggests that oxidative stress and endothelial activation (induced expression of adhesion molecules) of vital organ vasculatures are key, early steps in the pathogenesis. We aimed to ascertain the role and mechanism(s) of enhanced extracellular superoxide dismutase (EcSOD) expression in skeletal muscle in protection against MODS induced by endotoxemia. We showed that EcSOD overexpressed in skeletal muscle-specific transgenic mice (TG) redistributes to other peripheral organs through the circulation and enriches at the endothelium of the vasculatures. TG mice are resistant to endotoxemia (induced by lipopolysaccharide [LPS] injection) in developing MODS with significantly reduced mortality and organ damages compared with the wild type littermates (WT). Heterogenic parabiosis between TG and WT mice conferred a significant protection to WT mice, whereas mice with R213G knock-in mutation, a human single nucleotide polymorphism leading to reduced binding EcSOD in peripheral organs, exacerbated the organ damages. Mechanistically, EcSOD inhibits vascular cell adhesion molecule 1 expression and inflammatory leukocyte adhesion to the vascular wall of vital organs, blocking an early step of the pathology in organ damage under endotoxemia. Therefore, enhanced expression of EcSOD in skeletal muscle profoundly protects against MODS by inhibiting endothelial activation and inflammatory cell adhesion, which could be a promising therapy for MODS.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740866PMC
December 2017

Lungs donated after circulatory death and prolonged warm ischemia are transplanted successfully after enhanced ex vivo lung perfusion using adenosine A2B receptor antagonism.

J Thorac Cardiovasc Surg 2017 11 12;154(5):1811-1820. Epub 2017 Apr 12.

Department of Surgery, University of Virginia Health System, Charlottesville, Va. Electronic address:

Objective: The current supply of acceptable donor lungs is not sufficient for the number of patients awaiting transplantation. We hypothesized that ex vivo lung perfusion (EVLP) with targeted drug therapy would allow successful rehabilitation and transplantation of donation after circulatory death lungs exposed to 2 hours of warm ischemia.

Methods: Donor porcine lungs were procured after 2 hours of warm ischemia postcardiac arrest and subjected to 4 hours of cold preservation or EVLP. ATL802, an adenosine A receptor antagonist, was administered to select groups. Four groups (n = 4/group) were randomized: cold preservation (Cold), cold preservation with ATL802 during reperfusion (Cold + ATL802), EVLP (EVLP), and EVLP with ATL802 during ex vivo perfusion (EVLP + ATL802). Lungs subsequently were transplanted, reperfused, and assessed by measuring dynamic lung compliance and oxygenation capacity.

Results: EVLP + ATL802 significantly improved dynamic lung compliance compared with EVLP (25.0 ± 1.8 vs 17.0 ± 2.4 mL/cmHO, P = .04), and compared with cold preservation (Cold: 12.2 ± 1.3, P = .004; Cold + ATL802: 10.6 ± 2.0 mL/cmHO, P = .002). Oxygenation capacity was highest in EVLP (440.4 ± 37.0 vs Cold: 174.0 ± 61.3 mm Hg, P = .037). No differences in oxygenation or pulmonary edema were observed between EVLP and EVLP + ATL802. A significant decrease in interleukin-12 expression in tissue and bronchoalveolar lavage was identified between groups EVLP and EVLP + ATL802, along with less neutrophil infiltration.

Conclusions: Severely injured donation after circulatory death lungs subjected to 2 hours of warm ischemia are transplanted successfully after enhanced EVLP with targeted drug therapy. Increased use of lungs after uncontrolled donor cardiac death and prolonged warm ischemia may be possible and may improve transplant wait list times and mortality.
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http://dx.doi.org/10.1016/j.jtcvs.2017.02.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743073PMC
November 2017

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop.

JCI Insight 2017 May 4;2(9). Epub 2017 May 4.

Department of Medicine, Stanford University School of Medicine/VA Palo Alto Health Care System, Stanford, California, USA.

Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models.
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http://dx.doi.org/10.1172/jci.insight.93121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414568PMC
May 2017

Ex Vivo Lung Perfusion Rehabilitates Sepsis-Induced Lung Injury.

Ann Thorac Surg 2017 Jun 21;103(6):1723-1729. Epub 2017 Apr 21.

Department of Surgery, University of Virginia, Charlottesville, Virginia. Electronic address:

Background: Sepsis is the number one cause of lung injury in adults. Ex vivo lung perfusion (EVLP) is gaining clinical acceptance for donor lung evaluation and rehabilitation and may expand the use of marginal organs for transplantation. We hypothesized that 4 hours of normothermic EVLP would improve compliance and oxygenation in a porcine model of sepsis-induced lung injury.

Methods: We used intravenous lipopolysaccharide (LPS) to induce a systemic inflammatory response in a porcine model of lung injury. Two groups of 4 animals each received a 2-hour infusion of LPS through the external jugular vein. Serial measurements of blood gases were performed every 30 minutes until the partial pressure of oxygen/fraction of inspired oxygen ratio dropped below 150 on two consecutive readings. Lungs were then randomized to treatment with 4 hours of normothermic EVLP with STEEN Solution (XVIVO Perfusion Inc, Englewood, CO) or 4 additional hours of in vivo perfusion (control). Airway pressures and blood gases were recorded for calculation of dynamic lung compliance and partial pressure of oxygen/fraction of inspired oxygen ratios. EVLP was performed with hourly recruitment maneuvers and oxygen challenge.

Results: All animals reached a partial pressure of oxygen/fraction of inspired oxygen ratio of less than 150 mm Hg within 3 hours after start of the LPS infusion. Oxygenation and compliance in the control animals continued to decline during the 4-hour in vivo perfusion period, and 3 of the 4 animals died of severe hypoxia within 4 hours. The EVLP group demonstrated significant improvements hour 1 to hour 4 in oxygenation (365.8 ± 53.0 vs 584.4 ± 21.0 mm Hg, p = 0.02) and dynamic compliance (9.0 ± 2.8 vs 15.0 ± 3.6, p = 0.02 mL/cm HO).

Conclusions: EVLP successfully rehabilitated LPS-induced lung injury in this preclinical porcine model and may thus provide a means to rehabilitate many types of acute lung injury.
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http://dx.doi.org/10.1016/j.athoracsur.2017.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438908PMC
June 2017

Airway pressure release ventilation during ex vivo lung perfusion attenuates injury.

J Thorac Cardiovasc Surg 2017 01 22;153(1):197-204. Epub 2016 Sep 22.

Department of Surgery, University of Virginia, Charlottesville, Va. Electronic address:

Objective: Critical organ shortages have resulted in ex vivo lung perfusion gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of donation after circulatory death organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation during ex vivo lung perfusion improves lung function after transplantation.

Methods: Two groups (n = 4 animals/group) of porcine donation after circulatory death donor lungs were procured after hypoxic cardiac arrest and a 2-hour period of warm ischemia, followed by a 4-hour period of ex vivo lung perfusion rehabilitation with standard conventional volume-based ventilation or pressure-based airway pressure release ventilation. Left lungs were subsequently transplanted into recipient animals and reperfused for 4 hours. Blood gases for partial pressure of oxygen/inspired oxygen fraction ratios, airway pressures for calculation of compliance, and percent wet weight gain during ex vivo lung perfusion and reperfusion were measured.

Results: Airway pressure release ventilation during ex vivo lung perfusion significantly improved left lung oxygenation at 2 hours (561.5 ± 83.9 mm Hg vs 341.1 ± 136.1 mm Hg) and 4 hours (569.1 ± 18.3 mm Hg vs 463.5 ± 78.4 mm Hg). Likewise, compliance was significantly higher at 2 hours (26.0 ± 5.2 mL/cm HO vs 15.0 ± 4.6 mL/cm HO) and 4 hours (30.6 ± 1.3 mL/cm HO vs 17.7 ± 5.9 mL/cm HO) after transplantation. Finally, airway pressure release ventilation significantly reduced lung edema development on ex vivo lung perfusion on the basis of percentage of weight gain (36.9% ± 14.6% vs 73.9% ± 4.9%). There was no difference in additional edema accumulation 4 hours after reperfusion.

Conclusions: Pressure-directed airway pressure release ventilation strategy during ex vivo lung perfusion improves the rehabilitation of severely injured donation after circulatory death lungs. After transplant, these lungs demonstrate superior lung-specific oxygenation and dynamic compliance compared with lungs ventilated with standard conventional ventilation. This strategy, if implemented into clinical ex vivo lung perfusion protocols, could advance the field of donation after circulatory death lung rehabilitation to expand the lung donor pool.
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http://dx.doi.org/10.1016/j.jtcvs.2016.09.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164862PMC
January 2017

Donation After Circulatory Death Lungs Transplantable Up to Six Hours After Ex Vivo Lung Perfusion.

Ann Thorac Surg 2016 Dec 7;102(6):1845-1853. Epub 2016 Sep 7.

Department of Surgery, University of Virginia Health System, Charlottesville, Virginia. Electronic address:

Background: Despite the critical need for donor lungs, logistic and geographic barriers hinder lung utilization. We hypothesized that lungs donated after circulatory death subjected to 6 hours of cold preservation after ex vivo lung perfusion (EVLP) would have similar outcomes after transplantation as lungs transplanted immediately after EVLP, and that both would perform superiorly compared with lungs transplanted immediately after procurement.

Methods: Donor porcine lungs were procured after circulatory death and 15 minutes of warm ischemia. Three groups (n = 5 per group) were randomized: immediate left lung transplantation (Immediate group), EVLP for 4 hours followed by transplantation (EVLP group), or EVLP for 4 hours followed by 6 hours of cold preservation followed by transplantation (EVLP+Cold group). Lungs were reperfused for 2 hours before obtaining pulmonary vein samples for partial pressure of oxygen/fraction of inspired oxygen ratio calculations, airway pressures for compliance measurements, and wet/dry weight ratios.

Results: The partial pressure of oxygen/fraction of inspired oxygen ratios in the EVLP and EVLP+Cold groups were significantly improved compared with those in the Immediate group (429.7 ± 51.8 and 436.7 ± 48.2 versus 117.4 ± 22.9 mm Hg, respectively). In addition, dynamic compliance was significantly improved in the EVLP and EVLP+Cold groups compared with immediate group (26.2 ± 4.2 and 27.9 ± 3.5 versus 11.1 ± 2.4 mL/cmHO, respectively). There were no differences in oxygenation capacity or dynamic compliance between the EVLP and EVLP+Cold groups. Inflammatory cytokine levels were significantly lower in the EVLP and EVLP+Cold groups.

Conclusions: Lungs donated after circulatory death can be successfully transplanted as much as 6 hours after EVLP. Cold preservation of lungs after ex vivo assessment and rehabilitation may improve organ allocation, even to distant recipients, without compromising allograft function.
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http://dx.doi.org/10.1016/j.athoracsur.2016.06.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112144PMC
December 2016

Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A2B Receptor Antagonism.

Ann Thorac Surg 2016 Aug 22;102(2):385-393. Epub 2016 Apr 22.

Department of Surgery, University of Virginia, Charlottesville, VA.

Background: Ischemia-reperfusion injury (IRI) is a major source of morbidity and mortality after lung transplantation. We previously demonstrated a proinflammatory role of adenosine A2B receptor (A2BR) in lung IR injury. The current study tests the hypothesis that A2BR antagonism is protective of ischemic lungs after in vivo reperfusion or ex vivo lung perfusion (EVLP).

Methods: Mice underwent lung IR with or without administration of ATL802, a selective A2BR antagonist. A murine model of EVLP was also used to evaluate rehabilitation of donation after circulatory death (DCD) lungs. DCD lungs underwent ischemia, cold preservation, and EVLP with Steen solution with or without ATL802. A549 human type 2 alveolar epithelial cells were exposed to hypoxia-reoxygenation (HR) (3 hours/1 hour) with or without ATL802 treatment. Cytokines were measured in bronchoalveolar lavage (BAL) fluid and culture media by enzyme-linked immunoassay (ELISA).

Results: After IR, ATL802 treatment significantly improved lung function (increased pulmonary compliance and reduced airway resistance and pulmonary artery pressure) and significantly attenuated proinflammatory cytokine production, neutrophil infiltration, vascular permeability, and edema. ATL802 also significantly improved the function of DCD lungs after EVLP (increased compliance and reduced pulmonary artery pressure). After HR, A549 cells exhibited robust production of interleukin (IL)-8, a potent neutrophil chemokine, which was significantly attenuated by ATL802.

Conclusions: These results demonstrate that A2BR antagonism attenuates lung IRI and augments reconditioning of DCD lungs by EVLP. The protective effects of ATL802 may involve targeting A2BRs on alveolar epithelial cells to prevent IL-8 production. A2BR may be a novel therapeutic target for mitigating IRI to increase the success of lung transplantation.
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http://dx.doi.org/10.1016/j.athoracsur.2016.02.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958568PMC
August 2016