Genetically Modified Porcine-to-Human Cardiac Xenotransplantation.

A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).

Cost analysis of endovascular versus open repair in the treatment of thoracic aortic aneurysms.

OBJECTIVE: For descending thoracic aortic aneurysms (TAAs), it is generally considered that thoracic endovascular aortic repairs (TEVARs) reduce operative morbidity and mortality compared with open surgical repair. However, long-term differences in survival of patients have not been demonstrated, and an increased need for aortic reintervention has been observed. Many assume that TEVAR becomes less cost-effective through time because of higher rates of reintervention and surveillance imaging. This study investigated midterm outcomes and hospital costs of TEVAR compared with open TAA repair. METHODS: This was a retrospective, single-institution review of elective TAA repairs between 2005 and 2012. Patient demographics, operative outcomes, reintervention rates, and hospital costs were assessed. The literature was also reviewed to determine commonly observed complication and reintervention rates for TEVAR and open repair. Monte Carlo simulation was used to model and to forecast hospital costs for TEVAR and open TAA repair up to 3 years after intervention. RESULTS: Our cohort consisted of 131 TEVARs and 27 open repairs. TEVAR patients were significantly older (67.2 vs 58.7 years old; P = .02) and trended toward a more severe comorbidity profile. Operative mortality for TEVAR and open repair was 5.3% and 3.7%, respectively (P = 1.0). There was a trend toward more complications in the TEVAR group, although not statistically significant (all P > .05). In-hospital costs were significantly greater in the TEVAR group ($52,008 vs $37,172; P = .001). However, cost modeling by use of reported complication and reintervention rates from the literature overlaid with our cost data produced a higher cost for the open group in-hospital ($55,109 vs $48,006) and at 3 years ($58,426 vs $52,825). Interestingly, TEVAR hospital costs, not reintervention rates, were the most significant driver of cost in the TEVAR group. CONCLUSIONS: Our institutional data showed a trend toward lower mortality and complication rates with open TAA repair, with significantly lower costs within this cohort compared with TEVAR. These findings were likely, at least in part, to be due to the milder comorbidity profile of these patients. In contrast, cost modeling by Monte Carlo simulation demonstrated lower costs with TEVAR compared with open repair at all time points up to 3 years after intervention. Our institutional data show that with appropriate selection of patients, open repair can be performed safely with low complication rates comparable to those of TEVAR. The cost model argues that despite the costs associated with more frequent surveillance imaging and reinterventions, TEVAR remains the more cost-effective option even years after TAA repair.

Early removal of urinary catheter after surgery requiring thoracic epidural: a prospective trial.

OBJECTIVES: To prevent urinary retention, urinary catheters commonly are removed only after thoracic epidural discontinuation after thoracotomy. However, prolonged catheterization increases the risk of infection. The purpose of this study was to determine the rates of urinary retention and catheter-associated infection after early catheter removal. DESIGN: This study described a prospective trial instituting an early urinary catheter removal protocol compared with a historic control group of patients. SETTING: The protocol was instituted at a single, academic thoracic surgery unit. PARTICIPANTS: The study group was comprised of patients undergoing surgery requiring thoracotomy who received an intraoperative epidural for postoperative pain control. INTERVENTIONS: An early urinary catheter removal protocol was instituted prospectively, with all catheters removed on or before postoperative day 2. Urinary retention was determined by bladder ultrasound and treated with recatheterization. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were urinary retention rate, defined as bladder volume>400 mL, and urinary tract infection rate. Results were compared with a retrospective cohort of 210 consecutive patients who underwent surgery before protocol initiation. Among the 101 prospectively enrolled patients, urinary retention rate was higher (26.7% v 12.4%, p = 0.003), while urinary tract infection rate improved moderately (1% v 3.8%, p = 0.280). CONCLUSIONS: Early removal of urinary catheters with thoracic epidurals in place is associated with a high incidence of urinary retention. However, an early catheter removal protocol may play a role in a multifaceted approach to reducing the incidence of catheter-associated urinary tract infections.

Nonagenarians undergoing cardiac surgery.

BACKGROUND: As life expectancy continues to rise and cardiac surgical outcomes improve, the number of nonagenarian (age > 90 years) patients undergoing cardiac operations is increasing. However, little has been reported on cardiac surgical outcomes in this select patient population. The purpose of this study was to examine current cardiac surgical outcomes for nonagenarian patients and determine the impact of extreme age on contemporary risk calculations. STUDY DESIGN: From 2002 to 20012, 61,303 patients underwent cardiac operations as reported in a statewide Society of Thoracic Surgeons (STS) Adult Cardiac Surgery database, including 108 nonagenarians. Patient and operative factors, including STS Predicted Risk of Mortality (PROM), were analyzed in order to compare to estimated risk measures. RESULTS: Nonagenarian patients (median age = 92 years) had a high prevalence of preoperative cerebrovascular disease (23.1% [25/108]) and arrhythmia (55.6% [60/108]). Isolated coronary artery bypass grafting (CABG) (39.8% [43/108]) was the most common operation performed within this cohort, followed by aortic valve replacement (AVR: 35.2% [38/108], AVR + CABG 23.1% [25/108]) operations. Overall nonagenarian mortality was 13% [14/108] and was greatest for AVR. Among nonagenarians with calculated STS PROM, observed to expected (O:E) ratios for mortality ranged from 1.45 to 2.65 annually over the study period. CONCLUSIONS: Nonagenarian patients represent a high-risk, elderly patient population with higher morbidity than predicted. Mortality is greatest following aortic valve operations. These results suggest that current risk calculations may underestimate the impact of extreme age on perioperative mortality.

Pulmonary thromboendarterectomy in hospitalized versus elective patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVE: We sought to characterize outcomes in patients undergoing pulmonary thromboendarterectomy electively versus after acute presentation. METHODS: This is a retrospective analysis of patients who underwent pulmonary thromboendarterectomy from October 2015 to April 2022. Patients were divided into 2 groups depending on elective surgery or surgery during the same hospitalization as their presentation. RESULTS: In total, 69 patients were included: 45 in the hospitalized group and 24 in the elective group. Patients in the hospitalized group were less likely to have chronic lung disease, history of pulmonary embolism and hypertension, be on anticoagulation and medication for pulmonary hypertension, and present with >1 month of respiratory symptoms. They were more likely to have worse preoperative right ventricular function. Among other demographics, risk factors for venous thromboembolism were similar between both groups. Thirteen patients in the hospitalized group required preoperative extracorporeal membrane oxygenation. There was no difference in disease classification and operative, cardiopulmonary bypass, and hypothermic circulatory arrest durations between both groups. Postoperative complications were similar between both groups, except for greater frequency of deep vein thrombosis in the hospitalized group (26.7% vs 4.2%, P = .03). In-hospital and intensive care unit length of stay were similar between both groups. Overall, in-hospital mortality was 4.3% and was similar between both groups; P = .28. CONCLUSIONS: Our series shows that pulmonary thromboendarterectomy can be safely performed in patients presenting acutely, with comparable postoperative complications and in-hospital mortality to an elective setting. Such patients present with worse right ventricular function, sometimes requiring temporary mechanical support.

Eosinophils restrain humoral alloimmunity after lung transplantation.

While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils' role in alloimmunity. Due to their prevalence in the lung, and their defined role in other pulmonary pathologies such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody-secreting cell differentiation and resulted in de novo generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD-1+ T follicular helper (Tfh) cells, which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh cell generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naive CD4+ T cells. Our data thus describe what we believe is a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggest that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.

Primary payer status is associated with mortality and resource utilization for coronary artery bypass grafting.

BACKGROUND: Medicaid and uninsured populations are a significant focus of current healthcare reform. We hypothesized that outcomes after coronary artery bypass grafting (CABG) in the United States is dependent on primary payer status. METHODS AND RESULTS: From 2003 to 2007, 1,250,619 isolated CABG operations were evaluated using the Nationwide Inpatient Sample (NIS) database. Patients were stratified by primary payer status: Medicare, Medicaid, uninsured, and private insurance. Hierarchical multiple regression models were applied to assess the effect of primary payer status on postoperative outcomes. Unadjusted mortality for Medicare (3.3%), Medicaid (2.4%), and uninsured (1.9%) patients were higher compared with private insurance patients (1.1%, P<0.001). Unadjusted length of stay was longest for Medicaid patients (10.9 ± 0.04 days) and shortest for private insurance patients (8.0 ± 0.01 days, P<0.001). Medicaid patients accrued the highest unadjusted total costs ($113 380 ± 386, P<0.001). Importantly, after controlling for patient risk factors, income, hospital features, and operative volume, Medicaid (odds ratio, 1.82; P<0.001) and uninsured (odds ratio, 1.62; P<0.001) payer status independently conferred the highest adjusted odds of in-hospital mortality. In addition, Medicaid payer status was associated with the longest adjusted length of stay and highest adjusted total costs (P<0.001). CONCLUSIONS: Medicaid and uninsured payer status confers increased risk adjusted in-hospital mortality for patients undergoing coronary artery bypass grafting operations. Medicaid was further associated with the greatest adjusted length of stay and total costs despite risk factors. Possible explanations include delays in access to care or disparate differences in health maintenance.

Influence of hemodialysis on clinical outcomes after lung transplantation.

BACKGROUND: Chronic renal failure after lung transplantation is associated with significant morbidity. However, the significance of acute kidney injury (AKI) after lung transplantation remains unclear and poorly studied. We hypothesized that hemodialysis (HD)-dependent AKI after lung transplantation is associated with significant mortality. MATERIALS AND METHODS: We performed a retrospective review of all patients undergoing lung transplantation from July 1991 to July 2009 at our institution. Recipients with AKI (creatinine > 3 mg/dL) were identified. We compared recipients without AKI versus recipients with and without HD-dependent AKI. Kaplan-Meier survival curves were compared by log rank test. RESULTS: Of 352 lung transplant recipients reviewed at our institution, 17 developed non-HD-dependent AKI (5%) and 16 developed HD-dependent AKI (4.6%). Cardiopulmonary bypass was significantly higher in patients with HD-dependent AKI. None of the recipients who required HD had recovery of renal function. The 30-day mortality was significantly greater in recipients requiring HD (63% versus 0%; P < 0.0001). One-year mortality after transplantation was significantly increased in recipients with HD-dependent AKI compared with those with non-HD-dependent AKI (87.5% versus 17.6%; P < 0.001). CONCLUSIONS: Hemodialysis is associated with mortality after lung transplantation. Fortunately, AKI that does not progress to HD commonly resolves and has a better overall survival. Avoidance, if possible, of cardiopulmonary bypass may attenuate the incidence of AKI. Aggressive measures to identify and treat early postoperative renal dysfunction and prevent progression to HD may improve outcomes after lung transplantation.

Monitoring regulatory T cells as a prognostic marker in lung transplantation.

Lung transplantation is the major surgical procedure, which restores normal lung functioning and provides years of life for patients suffering from major lung diseases. Lung transplant recipients are at high risk of primary graft dysfunction, and chronic lung allograft dysfunction (CLAD) in the form of bronchiolitis obliterative syndrome (BOS). Regulatory T cell (Treg) suppresses effector cells and clinical studies have demonstrated that Treg levels are altered in transplanted lung during BOS progression as compared to normal lung. Here, we discuss levels of Tregs/FOXP3 gene expression as a crucial prognostic biomarker of lung functions during CLAD progression in clinical lung transplant recipients. The review will also discuss Treg mediated immune tolerance, tissue repair, and therapeutic strategies for achieving in-vivo Treg expansion, which will be a potential therapeutic option to reduce inflammation-mediated graft injuries, taper the toxic side effects of ongoing immunosuppressants, and improve lung transplant survival rates.

Regadenoson Reduces Soluble Receptor for Advanced Glycation End-Products in Lung Recipients.

BACKGROUND: The selective adenosine A2A receptor (A2AR) agonist regadenoson reduces inflammation due to lung ischemia-reperfusion injury (IRI). The objective of this study was to investigate molecular and cellular mechanisms by which regadenoson reduces IRI in lung transplant recipients. METHODS: Fourteen human lung transplant recipients were infused for 12 hours with regadenoson and 7 more served as untreated controls. Plasma levels of high mobility group box 1 and its soluble receptor for advanced glycation end-products (sRAGE) were measured by Luminex. Matrix metalloproteinase (MMP) 2 and 9 were measured by gelatin zymography. Tissue inhibitor of metalloproteinase 1 was measured by mass spectroscopy. A2AR expression on leukocytes was analyzed by flow cytometry. MMP-9-mediated cleavage of RAGE was evaluated using cultured macrophages in vitro. RESULTS: Regadenoson treatment during lung transplantation significantly reduced levels of MMP-9 (P < .05), but not MMP-2, and elevated levels of tissue inhibitor of metalloproteinase 1 (P < .05), an endogenous selective inhibitor of MMP-9. Regadenoson infusion significantly reduced plasma levels of sRAGE (P < .05) during lung reperfusion compared with control subjects. A2AR expression was highest on invariant natural killer T cells and higher on monocytes than other circulating immune cells (P < .05). The shedding of RAGE from cultured monocytes/macrophages was increased by MMP-9 stimulation and reduced by an MMP inhibitor or by A2AR agonists, regadenoson or ATL146e. CONCLUSIONS: In vivo and in vitro studies suggest that A2AR activation reduces sRAGE in part by inhibiting MMP-9 production by monocytes/macrophages. These results suggest a novel molecular mechanism by which A2AR agonists reduce primary graft dysfunction.

Regadenoson for the treatment of COVID-19: A five case clinical series and mouse studies.

BACKGROUND: Adenosine inhibits the activation of most immune cells and platelets. Selective adenosine A2A receptor (A2AR) agonists such as regadenoson (RA) reduce inflammation in most tissues, including lungs injured by hypoxia, ischemia, transplantation, or sickle cell anemia, principally by suppressing the activation of invariant natural killer T (iNKT) cells. The anti-inflammatory effects of RA are magnified in injured tissues due to induction in immune cells of A2ARs and ecto-enzymes CD39 and CD73 that convert ATP to adenosine in the extracellular space. Here we describe the results of a five patient study designed to evaluate RA safety and to seek evidence of reduced cytokine storm in hospitalized COVID-19 patients. METHODS AND FINDINGS: Five COVID-19 patients requiring supplemental oxygen but not intubation (WHO stages 4-5) were infused IV with a loading RA dose of 5 µg/kg/h for 0.5 h followed by a maintenance dose of 1.44 µg/kg/h for 6 hours, Vital signs and arterial oxygen saturation were recorded, and blood samples were collected before, during and after RA infusion for analysis of CRP, D-dimer, circulating iNKT cell activation state and plasma levels of 13 proinflammatory cytokines. RA was devoid of serious side effects, and within 24 hours from the start of infusion was associated with increased oxygen saturation (93.8 ± 0.58 vs 96.6 ± 1.08%, P<0.05), decreased D-dimer (754 ± 17 vs 518 ± 98 ng/ml, P<0.05), and a trend toward decreased CRP (3.80 ± 1.40 vs 1.98 ± 0.74 mg/dL, P = 0.075). Circulating iNKT cells, but not conventional T cells, were highly activated in COVID-19 patients (65% vs 5% CD69+). RA infusion for 30 minutes reduced iNKT cell activation by 50% (P<0.01). RA infusion for 30 minutes did not influence plasma cytokines, but infusion for 4.5 or 24 hours reduced levels of 11 of 13 proinflammatory cytokines. In separate mouse studies, subcutaneous RA infusion from Alzet minipumps at 1.44 µg/kg/h increased 10-day survival of SARS-CoV-2-infected K18-hACE2 mice from 10 to 40% (P<0.001). CONCLUSIONS: Infused RA is safe and produces rapid anti-inflammatory effects mediated by A2A adenosine receptors on iNKT cells and possibly in part by A2ARs on other immune cells and platelets. We speculate that iNKT cells are activated by release of injury-induced glycolipid antigens and/or alarmins such as IL-33 derived from virally infected type II epithelial cells which in turn activate iNKT cells and secondarily other immune cells. Adenosine released from hypoxic tissues, or RA infused as an anti-inflammatory agent decrease proinflammatory cytokines and may be useful for treating cytokine storm in patients with Covid-19 or other inflammatory lung diseases or trauma.

Acute hyperglycemic exacerbation of lung ischemia-reperfusion injury is mediated by receptor for advanced glycation end-products signaling.

The effects of acute hyperglycemia on lung ischemia-reperfusion (IR) injury and the role of receptor for advanced glycation end-products (RAGE) signaling in this process are unknown. The objective of this study was twofold: (1) evaluate the impact of acute hyperglycemia on lung IR injury; and (2) determine if RAGE signaling is a mechanism of hyperglycemia-enhanced IR injury. We hypothesized that acute hyperglycemia worsens lung IR injury through a RAGE signaling mechanism. C57BL/6 wild-type (WT) and RAGE knockout (RAGE (-/-)) mice underwent sham thoracotomy or lung IR (1-h left hilar occlusion and 2-h reperfusion). Acute hyperglycemia was established by dextrose injection 30 minutes before ischemia. Lung injury was assessed by measuring lung function, cytokine expression in bronchoalveolar lavage fluid, leukocyte infiltration, and microvascular permeability via Evans blue dye. Mean blood glucose levels doubled in hyperglycemic mice 30 minutes after dextrose injection. Compared with IR in normoglycemic mice, IR in hyperglycemic mice significantly enhanced lung dysfunction, cytokine expression (TNF-α, keratinocyte chemoattractant, IL-6, monocyte chemotactic protein-1, regulated upon activation, normal T cell expressed and secreted), leukocyte infiltration, and microvascular permeability. Lung injury and dysfunction after IR were attenuated in normoglycemic RAGE (-/-) mice, and hyperglycemia failed to exacerbate IR injury in RAGE (-/-) mice. Thus, this study demonstrates that acute hyperglycemia exacerbates lung IR injury, whereas RAGE deficiency attenuates IR injury and also prevents exacerbation of IR injury in an acute hyperglycemic setting. These results suggest that hyperglycemia-enhanced lung IR injury is mediated, at least in part, by RAGE signaling, and identifies RAGE as a potential, novel therapeutic target to prevent post-transplant lung IR injury.

Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model.

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.

Differential gender- and species-specific formation of aneurysms using a novel method of inducing abdominal aortic aneurysms.

BACKGROUND: The objective of this study was to test a novel model of inducing abdominal aortic aneurysms (AAAs) in different mouse strains and genders. MATERIALS AND METHODS: Male and female C57BL/6 and B6129 mice (n = 5 per group) underwent periaortic dissection and porcine pancreatic elastase (30 µL) or inactivated elastase application (5 min) to the aorta. Aortic measurements were taken on days 0 and 14. Aortic samples were analyzed for histology and zymography for matrix metalloproteinase (MMP) activity. Comparison statistics were performed using unpaired t-test. RESULTS: AAA phenotype (50% aortic increase) occurred in external elastase-treated males (100%) and females (90%). No control animals developed AAAs. The aortic diameter was larger in C57BL/6 and B6129 elastase-treated versus control males (P = 0.0028 and P < 0.0001, respectively) and females (P < 0.0001 and P = 0.0458, respectively). Histology verified phenotype via disrupted internal elastic laminae. Macrophage counts in elastase-treated animals were >6-fold higher than in controls (all groups significant). MMP9 activity was greater in elastase-treated males and females in C57BL/6 (P = 0.0031, P = 0.0004) and B6129 (P = 0.025, P = 0.2) mice; MMP2 activity was greater in C57BL/6 versus B6129 male elastase-treated mice. CONCLUSIONS: This rodent model produced AAAs in both genders and strains of mice. This model is simple, has little variability, and occurs in the infrarenal aorta, substantiating the external elastase model for future studies.

Natural killer T cell-derived IL-17 mediates lung ischemia-reperfusion injury.

RATIONALE: We recently implicated a role for CD4(+) T cells and demonstrated elevated IL-17A expression in lung ischemia-reperfusion (IR) injury. However, identification of the specific subset of CD4(+) T cells and their mechanistic role in IR injury remains unknown. OBJECTIVES: We tested the hypothesis that invariant natural killer T (iNKT) cells mediate lung IR injury via IL-17A signaling. METHODS: Mice underwent lung IR via left hilar ligation. Pulmonary function was measured using an isolated lung system. Lung injury was assessed by measuring edema (wet/dry weight) and vascular permeability (Evans blue dye). Inflammation was assessed by measuring proinflammatory cytokines in lungs, and neutrophil infiltration was measured by immunohistochemistry and myeloperoxidase levels. MEASUREMENTS AND MAIN RESULTS: Pulmonary dysfunction (increased airway resistance and pulmonary artery pressure and decreased pulmonary compliance), injury (edema, vascular permeability), and inflammation (elevated IL-17A; IL-6; tumor necrosis factor-α; monocyte chemotactic protein-1; keratinocyte-derived chemokine; regulated upon activation, normal T-cell expressed and secreted; and neutrophil infiltration) after IR were attenuated in IL-17A(-/-) and Rag-1(-/-) mice. Anti-IL-17A antibody attenuated lung dysfunction in wild-type mice after IR. Reconstitution of Rag-1(-/-) mice with wild-type, but not IL-17A(-/-), CD4(+) T cells restored lung dysfunction, injury, and inflammation after IR. Lung dysfunction, injury, IL-17A expression, and neutrophil infiltration were attenuated in Jα18(-/-) mice after IR, all of which were restored by reconstitution with wild-type, but not IL-17A(-/-), iNKT cells. Flow cytometry and enzyme-linked immunosorbent spot assay confirmed IL-17A production by iNKT cells after IR. CONCLUSIONS: These results demonstrate that CD4(+) iNKT cells play a pivotal role in initiating lung injury, inflammation, and neutrophil recruitment after IR via an IL-17A-dependent mechanism.

Extracorporeal life support as a bridge to lung transplantation: Where are we now?

The number of lung transplant procedures performed internationally is increasing but the donor organ pool is insufficient to meet demand and waiting list mortality is unacceptably high. As survival rates for patients with acute respiratory distress syndrome managed on extracorporeal life support (ECLS) have steadily improved, a potential role for ECLS to support critically ill patients awaiting a donor organ match has emerged. We explore the rapidly evolving landscape of ECLS as a bridge to lung transplantation with review of the patient selection criteria, predictors of survival, modes of pre and peri-transplant support, and the importance of a holistic multidisciplinary approach to care. Finally, we consider innovations that are envisaged to increase the accessibility, safety, and effectiveness of ECLS delivery for future lung transplant candidates.

Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation.

Ischemia-reperfusion (IR) injury following lung transplantation remains a major source of early morbidity and mortality. Histologically, this inflammatory process is characterized by neutrophil infiltration and activation. We previously reported that lung IR injury was significantly attenuated in plasminogen activator inhibitor-1-deficient mice. In this study, we explored the potential role of tissue plasminogen activator (tPA) in a mouse lung IR injury model. As a result, tPA knockout (KO) mice were significantly protected from lung IR injury through several mechanisms. At the cellular level, tPA KO specifically blocked neutrophil extravasation into the interstitium, and abundant homotypic neutrophil aggregation (HNA) was detected in the lung microvasculature of tPA KO mice after IR. At the molecular level, inhibition of neutrophil extravasation was associated with reduced expression of platelet endothelial cell adhesion molecule-1 mediated through the tPA/ LDL receptor-related protein/NF-κB signaling pathway, whereas increased P-selectin triggered HNA. At the functional level, tPA KO mice incurred significantly decreased vascular permeability and improved lung function following IR. Protection from lung IR injury in tPA KO mice occurs through a fibrinolysis-independent mechanism. These results suggest that tPA could serve as an important therapeutic target for the prevention and treatment of acute IR injury after lung transplantation.

The incidence of pulmonary neoplasms discovered by serial computed tomography scanning after endovascular abdominal aortic aneurysm repair.

OBJECTIVES: Serial computed tomography (CT) scanning is routinely used to follow up endovascular exclusion of abdominal aortic aneurysms (AAAs). Nonvascular diseases can be identified, and these exams include images of the lung bases, which can provide information that leads to the diagnosis of pulmonary neoplasms. This study was conducted to determine the rate and type of pulmonary-based oncologic diseases identified by serial CT scanning of patients with endovascular repair of AAAs. METHODS: A retrospective review of 138 consecutive patients receiving endovascular AAA exclusion during an 8-year period was performed. Length of follow-up and number of CT scans performed was recorded. CT characteristics of the lesion (size, character, and suspicion of malignancy), type of biopsy procedure performed, and final pathologic diagnosis were collected. Oncologic treatments and survival length were also evaluated. RESULTS: Pulmonary lesions were found in 25 patients (18%), of whom 5 (4%) died during follow-up, and 13 (9%) had stable, subcentimeter lesions and continue to have surveillance from vascular specialists only. Seven patients (5%) with pulmonary lesions were referred for evaluation by thoracic surgeons. Six patients (4%) underwent biopsy of the lesion and were diagnosed with cancer. One patient refused a biopsy and is being monitored with serial CT scans. Four lung cancers (1 small cell and 3 non-small cell), one primary pulmonary carcinoid tumor, and one B-cell lymphoma were discovered. No changes were noted in the lesions in the patient receiving CT surveillance. More than half of the cancers were diagnosed in stage I, with a mean lesion diameter of 11 mm at biopsy. Of 25 patients with pulmonary nodules, 24 were men. The patients diagnosed with cancer are all still alive, with a mean survival length of 2.5 years (range, 0.5-6 years) after oncologic treatment. CONCLUSIONS: Serial CT scans may reveal a high rate of pulmonary malignancies in a population with AAAs. Attention to the incidental finding of pulmonary nodules on CT scans and arrangement of appropriate follow-up by the vascular surgeon is important for patients undergoing surveillance after endovascular AAA repair. These results indicate that aggressive management of these lesions (early thoracic surgery consultation and biopsy) is appropriate in this high-risk population and may offer early diagnosis and improved long-term survival.

Ex Vivo Lung Perfusion: Current Achievements and Future Directions.

There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation.

Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review.

Lung ischemia-reperfusion injury (LIRI) and primary graft dysfunction are leading causes of morbidity and mortality among lung transplant recipients. Although extensive research endeavors have been undertaken, few preventative and therapeutic treatments have emerged for clinical use. Novel strategies are still needed to improve outcomes after lung transplantation. In this review, we discuss the underlying mechanisms of transplanted LIRI, potential modifiable targets, current practices, and areas of ongoing investigation to reduce LIRI and primary graft dysfunction in lung transplant recipients.