CT imaging findings in lung transplant recipients with COVID-19.

OBJECTIVES: Our goal was to compare the chest computed tomography (CT) imaging findings of COVID-19 in lung transplant recipients (LTR) and a group of non-transplanted controls (NTC). METHODS: This retrospective study included 51 consecutive LTR hospitalized with COVID-19 from two centers. A total of 75 NTC were included for comparison. Images were classified regarding the standardized RSNA category, main pattern of lung attenuation, and longitudinal and axial distribution. Quantitative CT (QCT) analysis was performed to evaluate percentage of high attenuation areas (%HAA, threshold -250 to -700 HU). CT scoring was used to measure severity of parenchymal abnormalities. RESULTS: The imaging findings of COVID-19 in LTR were significantly different from controls regarding the RSNA classification and pattern of lung attenuation. LTR had a significantly higher proportion of patients with an indeterminate pattern on CT (0.31 vs. 0.11, p = 0.014). The most frequent pattern of attenuation in LTR was predominantly consolidation (0.39 vs. 0.22, p = 0.144) followed by a mixed pattern of ground-glass opacities (GGO) and consolidation (0.37 vs. 0.20, adjusted p = 0.102). On the other hand, the most common pattern in NTC was GGO predominant (0.58 vs. 0.24 of LTR, p = 0.001). LTR had significantly more severe parenchymal disease measured by CT score and %HAA by QCT (0.372 ± 0.08 vs. 0.148 ± 0.06, p < 0.001). CONCLUSION: The most frequent finding of COVID-19 in LTR is a predominant pattern of consolidation. Compared to NTC, LTR more frequently demonstrated an indeterminate pattern according to the RSNA classification and more extensive lung abnormalities on QCT and semi-quantitative scoring. KEY POINTS: • The most common CT finding of COVID-19 in LTR is a predominant pattern of consolidation followed by a mixed pattern of GGO and consolidation, while controls more often have a predominant pattern of GGO. • LTR more often presents with an indeterminate pattern of COVID-19 by RSNA classification than controls; therefore, molecular testing for COVID-19 is essential for LTR presenting with lower airway infection independently of imaging findings. • LTR had more extensive disease by semi-quantitative CT score and increased percentage areas of high attenuation on QCT.

Acute transcutaneous electrical stimulation (TES) augments esophageal contractility in patients with weak peristalsis.

BACKGROUND: Lung transplantation (LTx) remains controversial in patients with absent peristalsis (AP) given the increased risk for gastroesophageal reflux (GER), and chronic lung allograft dysfunction. Furthermore, specific treatments to facilitate LTx in those with AP have not been widely described. Transcutaneous Electrical Stimulation (TES) has been reported to improve foregut contractility in LTx patients and therefore we hypothesize that TES may augment the esophageal motility of patients with ineffective esophageal motility (IEM). METHODS: We included 49 patients, 14 with IEM, 5 with AP, and 30 with normal motility. All subjects underwent standard high-resolution manometry and intraluminal impedance (HRIM) with additional swallows as TES was delivered. RESULTS: TES induced a universal impedance change observable in real-time by a characteristic spike activity. TES significantly augmented the contractile vigor of the esophagus measured by the distal contractile integral (DCI) in patients with IEM [median DCI (IQR) 0 (238) mmHg-cm-s off TES vs. 333 (858) mmHg-cm-s on TES; p = .01] and normal peristalsis [median DCI (IQR) 1545 (1840) mmHg-cm-s off TES vs. 2109 (2082) mmHg-cm-s on TES; p = .01]. Interestingly, TES induced measurable contractile activity (DCI > 100 mmHg-cm-s) in three out of five patients with AP [median DCI (IQR) 0 (0) mmHg-cm-s off TES vs. 0 (182) mmHg-cm-s on TES; p < .001]. CONCLUSION: TES acutely augmented contractile vigor in patients with normal and weak/ AP. The use of TES may positively impact LTx candidacy, and outcomes for patients with IEM/AP. Nevertheless, further studies are needed to determine the long-term effects of TES in this patient population.

Laparoscopic Toupet fundoplication: a safe and effective anti-reflux option in lung transplant recipients.

BACKGROUND: Fundoplication is known to improve allograft outcomes in lung transplant recipients by reducing retrograde aspiration secondary to gastroesophageal reflux disease, a modifiable risk factor for chronic allograft dysfunction. Laparoscopic Nissen fundoplication has historically been the anti-reflux procedure of choice, but the procedure is associated with discernable rates of postoperative dysphagia and gas-bloat syndrome. Laparoscopic Toupet fundoplication, an alternate anti-reflux surgery with lower rates of foregut complications in the general population, is the procedure of choice on our institution's lung transplant protocol. In this work, we evaluated the efficacy and safety of laparoscopic Toupet fundoplication in our lung transplant recipients. METHODS: A prospective case series of 44 lung transplant recipients who underwent laparoscopic Toupet fundoplication by a single surgeon between September 2018 and November 2020 was performed. Preoperative and postoperative results from 24-h pH, esophageal manometry, gastric emptying, and pulmonary function studies were collected alongside severity of gastroesophageal reflux disease and other gastrointestinal symptoms. RESULTS: Median DeMeester score decreased from 25.9 to 5.4 after fundoplication (p < 0.0001), while percentage of time pH < 4 decreased from 7 to 1.1% (p < 0.0001). The severity of heartburn and regurgitation were also reduced (p < 0.0001 and p = 0.0029 respectively). Overall, pulmonary function, esophageal motility, gastric emptying, severity of bloating, and dysphagia were not significantly different post-fundoplication than pre-fundoplication. Patients with decreasing rates of FEV1 pre-fundoplication saw improvement in their rate of change of FEV1 post-fundoplication (p = 0.011). Median follow-up was 32.2 months post-fundoplication. CONCLUSIONS: Laparoscopic Toupet fundoplication provides objective pathologic acid reflux control and symptomatic gastroesophageal reflux improvement in lung transplant recipients while preserving lung function and foregut motility. Thus, laparoscopic Toupet fundoplication is a safe and effective antireflux surgery alternative in lung transplant recipients.

Lung transplantation for acute exacerbation of interstitial lung disease.

BACKGROUND: Acute exacerbations of interstitial lung diseases (AE-ILD) have a high mortality rate with no effective medical therapies. Lung transplantation is a potentially life-saving option for patients with AE-ILD, but its role is not well established. The aim of this study is to determine if this therapy during AE-ILD significantly affects post-transplant outcomes in comparison to those transplanted with stable disease. METHODS: We conducted a retrospective study of consecutive patients with AE-ILD admitted to our institution from 2015 to 2018. The comparison group included patients with stable ILD listed for lung transplant during the same period. The primary end-points were in-hospital mortality for patients admitted with AE-ILD and 1-year survival for the transplanted patients. RESULTS: Of 53 patients admitted for AE-ILD, 28 were treated with medical therapy alone and 25 underwent transplantation. All patients with AE-ILD who underwent transplantation survived to hospital discharge, whereas only 43% of the AE-ILD medically treated did. During the same period, 67 patients with stable ILD underwent transplantation. Survival at 1 year for the transplanted patients was not different for the AE-ILD group versus stable ILD group (96% vs 92.5%). The rates of primary graft dysfunction, post-transplant hospital length-of-stay and acute cellular rejection were similar between the groups. CONCLUSION: Patients with ILD transplanted during AE-ILD had no meaningful difference in overall survival, rate of primary graft dysfunction or acute rejection compared with those transplanted with stable disease. Our results suggest that lung transplantation can be considered as a therapeutic option for selected patients with AE-ILD.

Hyperammonemia After Lung Transplantation: Systematic Review and a Mini Case Series.

Background: Hyperammonemia after lung transplantation (HALT) is a rare but serious complication with high mortality. This systematic review delineates possible etiologies of HALT and highlights successful strategies used to manage this fatal complication. Methods: Seven biomedical databases and grey literature sources were searched using keywords relevant to hyperammonemia and lung transplantation for publications between 1995 and 2020. Additionally, we retrospectively analyzed HALT cases managed at our institution between January 2016 and August 2018. Results: The systematic review resulted in 18 studies with 40 individual cases. The mean peak ammonia level was 769 µmol/L at a mean of 14.1 days post-transplant. The mortality due to HALT was 57.5%. In our cohort of 120 lung transplants performed, four cases of HALT were identified. The mean peak ammonia level was 180.5 µmol/L at a mean of 11 days after transplantation. HALT in all four patients was successfully treated using a multimodal approach with an overall mortality of 25%. Conclusion: The incidence of HALT (3.3%) in our institution is comparable to prior reports. Nonetheless, ammonia levels in our cohort were not as high as previously reported and peaked earlier. We attributed these significant differences to early recognition and prompt institution of multimodal treatment approach.

Corrigendum: Hyperammonemia After Lung Transplantation: Systematic Review and a Mini Case Series.

[This corrects the article DOI: 10.3389/ti.2022.10433.].

Successful bridge to lung transplantation with transcatheter aortic valve replacement.

End-stage lung disease and advanced cardiac conditions are frequently seen together and represent a clinical dilemma. Even though both issues may be amenable to surgical management, combining lung transplant with surgical valve repair is rarely done and theoretically associated with increased morbidity and mortality risks, especially in elderly patients. Here, we describe 2 patients presenting with end-stage lung disease and significant aortic stenosis who were successfully bridged to lung transplant via transcatheter aortic valve replacement. Patient 1 was a 66-year-old man who underwent a double lung transplant 56 days after transcatheter aortic valve replacement. Patient 2 was a 70-year-old man who underwent a single right lung transplant 103 days after transcatheter aortic valve replacement. Both patients had uneventful postoperative courses and are alive at the 1-year time point with excellent performance status. This report suggests that transcatheter aortic valve replacement may favorably impact lung transplant candidacy for patients with end-stage lung disease in the setting of severe aortic stenosis, likely representing a better alternative to concomitant aortic valve replacement and lung transplant in elderly patients.

Pre-operative therapeutic plasma Exchange and intravenous immune globulin for the treatment of heparin induced thrombocytopenia in a lung transplant recipient.

Lung transplantation surgery often relies on the use of intraoperative extracorporeal membrane oxygenation (ECMO) and necessitates the need for high dose anticoagulation. Heparin induced thrombocytopenia complicates intraoperative anticoagulation management during lung transplant surgery requiring ECMO. Though other anticoagulants such as argatroban and bivalrudin are utilized for the treatment of Heparin Induced Thrombocytopenia (HIT), the lack of reversal agents makes it difficult to use these agents intraoperatively in cases with high bleeding risk. This is especially true in patients with end stage fibrotic lung disease with calcified mediastinal lymphadenopathy and pulmonary hypertension undergoing lung transplantation. Here we describe a case of HIT in a patient with Sarcoidosis listed for lung transplant who was treated with Therapeutic Plasma Exchange and Intravenous Immune globulin preoperatively and successfully underwent lung transplantation with the use of intraoperative venoarterial ECMO and heparin anticoagulation.

Nuances in the interpretation and utility of donor-derived cell-free DNA in lung transplantation following allogeneic hematopoietic stem cell transplantation - Case report.

Respiratory complications following allogeneic HSCT can lead to severe morbidity and mortality. Lung transplantation (LT) is a potential treatment for select patients with late-onset non-infectious pulmonary complications post-HSCT. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive biomarker for monitoring the health of allografts following LT. However, its utility in a multi-genome setting of LT after HSCT has not yet been clinically validated. Here we describe a case of a 75-year-old, male patient who underwent single-lung transplantation for BOS related to chronic GVHD and presented with persistently elevated dd-cfDNA levels. In a surveillance biopsy, the patient was diagnosed with mild acute cellular rejection at three months. The patient's lung function remained stable, and the reported dd-cfDNA levels decreased after the rejection episode but remained elevated above levels that would be considered quiescent for LT alone. In this unique setting, as 3 different genomes contributed to the dd-cfDNA% reported value, valuable insight was obtained by performing further analysis to separate the specific SNPs to identify the contribution of recipient, lung-donor, and HSCT-donor cfDNA. This study highlights the potential utility of dd-cfDNA in the multi-genome setting of lung transplant post-HSCT, nuances that need to be considered while interpreting the results, and its value in monitoring lung rejection.

Questionnaries for measuring fatigue and its impact on health perception in inflammatory bowel disease.

INTRODUCTION: fatigue impacts perceived health, but its importance in inflammatory bowel disease is not known. OBJECTIVES: to define the applicability of the fatigue measurement questionnaires and analyze it in patients with Crohn´s disease and ulcerative colitis. MATERIAL AND METHODS: in a first phase, the psychometric properties of 3 fatigue measurement questionnaires were determined in 99 patients: Daily Fatigue Impact Scale, Fatigue Severity Scale, and Modified Fatigue Impact Scale. In a second phase, fatigue status and its relationship to disease and quality of life was determined in 127 patients and 69 healthy controls. RESULTS: the first part of the study showed the applicability of the questionnaires listed in inflammatory bowel disease, the Daily Fatigue Impact Scale (DFIS) having the best correlation with the quality of life and clinical activity. In the second phase, significantly higher levels of fatigue were observed in active disease than in disease in remission and healthy controls (p < 0,05). The severity of fatigue was significantly correlated with quality of life (r = -0.66 and -0.72 between IBDQ-9 and DFIS and in Crohn´s disease and ulcerative colitis, respectively) and with disease activity (r = 0.25 and Crohn´s disease and ulcerative colitis, respectively, p < 0.05). CONCLUSIONS: in inflammatory bowel disease, fatigue measurement questionnaires have good properties and show that fatigue is an important manifestation of the disease, which has a significant impact on quality of life of patients.

The Highly Sensitized Recipient: Pretransplant and Posttransplant Considerations.

Highly sensitized patients, who are often black and Hispanic women, are less likely to be listed for lung transplant and are at higher risk for prolonged waitlist time and waitlist death. In this review, the authors discuss strategies for improving access to transplant in this population, including risk stratification of crossing pretransplant donor-specific antibodies, based on antibody characteristics. The authors also review institutional protocols, such as perioperative desensitization, for tailoring transplant immunosuppression in the highly sensitized population. The authors conclude with suggestions for future research, including development of novel donor-specific antibody-directed therapeutics.

A prospective examination of swallow and cough dysfunction after lung transplantation.

OBJECTIVES: Swallow and cough dysfunction are possible surgical complications of lung transplantation (LT). We examined voluntary cough strength, sensorimotor reflexive cough integrity, and swallow-related respiratory rate (RR) across swallowing safety and aspiration response groups in recovering LT recipients. METHODS: Forty-five LT recipients underwent flexible endoscopic evaluation of swallowing indexed by the validated Penetration Aspiration Scale. RR before and after a 3-ounce water drinking task was measured. Voluntary and reflexive cough screening were performed to index motor and sensory outcomes. T-tests, one-way ANOVAs, and chi-square (odds ratios) were used. RESULTS: 60% of patients exhibited laryngeal penetration (n = 27) and 40% demonstrated tracheal aspiration (n = 18); 72% (n = 13) demonstrated silent aspiration. Baseline RR was higher in aspirators versus non-aspirators (26.5 vs. 22.6, p = 0.04) and in silent aspirators compared to non-silent aspirators (27.9 vs. 20.7, p = 0.01). RR change post-swallowing did not differ between aspiration response groups; however, it was significantly higher in aspirators compared to non-aspirators (3 vs. -2, p = 0.02). Compared to non-silent aspirators, silent aspirators demonstrated reduced voluntary cough peak expiratory flow (PEF; 166 vs. 324 L/min, p = 0.01). PEF, motor and urge to cough reflex cough ratings did not differ between aspirators and non-aspirators. Silent aspirators demonstrated a 7.5 times higher odds of failing reflex cough screening compared to non-silent aspirators (p = 0.07). CONCLUSIONS: During the acute recovery period, all LT participants demonstrated some degree of unsafe swallowing and reduced voluntary cough strength. Silent aspirators exhibited elevated RR, reduced voluntary cough physiologic capacity to defend the airway, and a clinically distinguishable blunted motor response to reflex cough screening.

Incidence, risk factors, and sequelae of dysphagia mediated aspiration following lung transplantation.

BACKGROUND: We aimed to determine dysphagia profiles before and after lung transplantation (prevalence, incidence) and to examine predictors and health-related outcomes of aspiration in individuals undergoing lung transplantation. METHODS: A retrospective single-center study of consecutive adults undergoing lung transplantation and completing a postoperative videofluoroscopic swallowing study between 2017 and 2020 was conducted. The validated penetration aspiration scale indexed swallowing safety and clinical outcomes were extracted from electronic medical records. T-tests, chi square with odds ratios, and multivariable logistic regression were conducted. RESULTS: Two hundred five participants were identified who underwent lung transplantation and a postoperative swallowing exam. Of those who underwent both a pre- and postoperative swallowing exam (n = 170), preoperatively 83% demonstrated safe swallowing and 17% unsafe swallowing. Following lung transplantation, 16% demonstrated safe swallowing and 84% demonstrated unsafe swallowing (39% penetration, 45% aspiration). Independent predictors of postoperative aspiration were venous-venous extracorporeal membrane oxygenation (odds ratio [OR]: 6.7, confidence interval [CI]: 2.0-81.5) and reintubation (OR: 4.5, CI: 1.0-60.3), p < .05. Compared to non-aspirators, aspirators demonstrated higher odds of being discharged to a dependent care setting (OR: 2.3, CI: 1.2-4.5), p < .05. Aspirators spent significantly longer NPO (median = 138.0 hours, 25th percentile, 75th percentile = 75.7, 348.3) compared to non-aspirators (median = 85.0 hours, 25th percentile, 75th percentile = 48.0, 131.6, p < .001). CONCLUSIONS: Pre-existing dysphagia was low in this cohort of patients undergoing lung transplantation, however increased approximately 5-fold following lung transplantation and was associated with increased morbidity.

Pro-inflammatory IgG1 N-glycan signature correlates with primary graft dysfunction onset in COPD patients.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. The pathogenesis of COPD is complex; however, recent studies suggest autoimmune changes, characterized by the presence of autoantibodies to elastin and collagen, may contribute to disease status. COPD patients make up approximately 30% of all lung transplants (LTx) annually, however, little is known regarding the relationship between COPD-related autoantibodies and LTx outcomes. We hypothesized that COPD patients that undergo LTx and develop primary graft dysfunction (PGD) have altered circulating autoantibody levels and phenotypic changes as compared those COPD-LTx recipients that do not develop PGD. We measured total immunoglobulin and circulating elastin and collagen autoantibody levels in a cohort of COPD lung transplant recipients pre- and post-LTx. No significant differences were seen in total, elastin, or collagen IgM, IgG, IgG1, IgG2, IgG3, and IgG4 antibodies between PGD+ and PGD- recipients. Antibody function can be greatly altered by glycosylation changes to the antibody Fc region and recent studies have reported altered IgG glycosylation profiles in COPD patients. We therefore utilized a novel mass spectrometry-based multiplexed N-glycoprotein imaging approach and measured changes in IgG-specific antibody N-glycan structures. COPD-LTx recipients who developed PGD had significantly increased IgG1 N-glycan signatures as compared PGD- recipients. In conclusion, we show that immunoglobulin and autoreactive antibody levels are not significantly different in COPD LTx recipients that develop PGD. However, using a novel IgG glycomic analysis we were able to demonstrate multiple significant increases in IgG1 specific N-glycan signatures that were predictive of PGD development. Taken together, these data represent a potential novel method for identifying COPD patients at risk for PGD development and may provide clues to mechanisms by which antibody N-glycan signatures could contribute to antibody-mediated PGD pathogenesis.

Improvement of an additively manufactured subperiosteal implant structure design by finite elements based topological optimization.

To design a new subperiosteal implant structure for patients suffering from severe Maxillary Atrophy that lowers manufacturing cost, shortens surgical time and reduces patient trauma with regard to current implant structures. A 2-phase finite-element-based topology optimization process was employed with implants made from biocompatible materials via additive manufacturing. Five bite loading cases related to standard chewing, critical chewing force, and worst conditions of fastening were considered along with each specific result to establish the areas that needed to be subjected to fatigue strength optimization. The 2-phase topological optimization tested in this study performed better than the reference implant geometry in terms of both the structural integrity of the implant under tensile-compressive and fatigue strength conditions and the material constraints related to implant manufacturing conditions. It returns a nearly 28% lower volumetric geometry and avoids the need to use two upper fastening screws that are required with complex surgical procedures. The combination of topological optimization methods with the flexibility afforded by additively manufactured biocompatible materials, provides promising results in terms of cost reduction, minimizing the surgical trauma and implant installation impact on edentulous patients.

Successful Preoperative Optimization for Lung Transplantation With Transcatheter Mitral Valve Repair.

Surgically treatable valvular heart disease is common in patients with end-stage lung disease. Nevertheless, advanced lung disease is often seen as a contraindication to cardiac surgery, and severe valvular disease is seen as a contraindication to lung transplantation. This report describes the case of a patient presenting with very severe chronic obstructive pulmonary disease and severe mitral regurgitation who was managed with transcatheter mitral valve repair and who subsequently underwent successful lung transplantation. Critical valvular heart disease in patients with chronic respiratory failure may be amenable to transcatheter therapy, which may favorably affect lung transplantation candidacy.

ACR Appropriateness Criteria® Noncerebral Vasculitis.

Noncerebral vasculitis is a wide-range noninfectious inflammatory disorder affecting the vessels. Vasculitides have been categorized based on the vessel size, such as large-vessel vasculitis, medium-vessel vasculitis, and small-vessel vasculitis. In this document, we cover large-vessel vasculitis and medium-vessel vasculitis. Due to the challenges of vessel biopsy, imaging plays a crucial role in diagnosing this entity. While CTA and MRA can both provide anatomical details of the vessel wall, including wall thickness and enhancement in large-vessel vasculitis, FDG-PET/CT can show functional assessment based on the glycolytic activity of inflammatory cells in the inflamed vessels. Given the size of the vessel in medium-vessel vasculitis, invasive arteriography is still a choice for imaging. However, high-resolution CTA images can depict small-caliber aneurysms, and thus can be utilized in the diagnosis of medium-vessel vasculitis. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries.

BACKGROUND: Lung transplantation is a life-saving treatment for patients with end-stage lung disease; however, it is infrequently considered for patients with acute respiratory distress syndrome (ARDS) attributable to infectious causes. We aimed to describe the course of disease and early post-transplantation outcomes in critically ill patients with COVID-19 who failed to show lung recovery despite optimal medical management and were deemed to be at imminent risk of dying due to pulmonary complications. METHODS: We established a multi-institutional case series that included the first consecutive transplants for severe COVID-19-associated ARDS known to us in the USA, Italy, Austria, and India. De-identified data from participating centres-including information relating to patient demographics and pre-COVID-19 characteristics, pretransplantation disease course, perioperative challenges, pathology of explanted lungs, and post-transplantation outcomes-were collected by Northwestern University (Chicago, IL, USA) and analysed. FINDINGS: Between May 1 and Sept 30, 2020, 12 patients with COVID-19-associated ARDS underwent bilateral lung transplantation at six high-volume transplant centres in the USA (eight recipients at three centres), Italy (two recipients at one centre), Austria (one recipient), and India (one recipient). The median age of recipients was 48 years (IQR 41-51); three of the 12 patients were female. Chest imaging before transplantation showed severe lung damage that did not improve despite prolonged mechanical ventilation and extracorporeal membrane oxygenation. The lung transplant procedure was technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. Pathology of the explanted lungs showed extensive, ongoing acute lung injury with features of lung fibrosis. There was no recurrence of SARS-CoV-2 in the allografts. All patients with COVID-19 could be weaned off extracorporeal support and showed short-term survival similar to that of transplant recipients without COVID-19. INTERPRETATION: The findings from our report show that lung transplantation is the only option for survival in some patients with severe, unresolving COVID-19-associated ARDS, and that the procedure can be done successfully, with good early post-transplantation outcomes, in carefully selected patients. FUNDING: National Institutes of Health. VIDEO ABSTRACT.

MicroRNA-206 antagomiR‒enriched extracellular vesicles attenuate lung ischemia‒reperfusion injury through CXCL1 regulation in alveolar epithelial cells.

BACKGROUND: Our hypothesis is that the immunomodulatory capacities of mesenchymal stem cell‒derived extracellular vesicles (EVs) can be enhanced by specific microRNAs (miRNAs) to effectively attenuate post-transplant lung ischemia‒reperfusion (IR) injury. METHODS: The expression of miR-206 was analyzed in bronchoalveolar lavage (BAL) fluid of patients on Days 0 and 1 after lung transplantation. Lung IR injury was evaluated in C57BL/6 mice using a left lung hilar-ligation model with or without treatment with EVs or antagomiR-206‒enriched EVs. Murine lung tissue was used for miRNA microarray hybridization analysis, and cytokine expression, lung injury, and edema were evaluated. A donation after circulatory death and murine orthotopic lung transplantation model was used to evaluate the protection by enriched EVs against lung IR injury. In vitro studies analyzed type II epithelial cell activation after coculturing with EVs. RESULTS: A significant upregulation of miR-206 was observed in the BAL fluid of patients on Day 1 after lung transplantation compared with Day 0 and in murine lungs after IR injury compared with sham. Treatment with antagomiR-206‒enriched EVs attenuated lung dysfunction, injury, and edema compared with treatment with EVs alone after murine lung IR injury. Enriched EVs reduced lung injury and neutrophil infiltration as well as improved allograft oxygenation after murine orthotopic lung transplantation. Enriched EVs significantly decreased proinflammatory cytokines, especially epithelial cell‒dependent CXCL1 expression, in the in vivo and in vitro IR injury models. CONCLUSIONS: EVs can be used as biomimetic nanovehicles for protective immunomodulation by enriching them with antagomiR-206 to mitigate epithelial cell activation and neutrophil infiltration in the lungs after IR injury.

Alcohol primes the airway for increased interleukin-13 signaling.

BACKGROUND: Using an experimental model of airway fibrosis following lung transplantation, we recently showed that chronic alcohol ingestion by donor rats amplifies airway fibrosis in the recipient. Associated with alcohol-mediated amplification of airway fibrosis is increased transforming growth factor beta-1(TGFbeta(1)) and alpha-smooth muscle actin expression. Other studies have shown that interleukin-13 (IL-13) modulates TGFbeta(1) signaling during experimentally-induced airway fibrosis. Therefore, we hypothesized that IL-13 is a component of alcohol-mediated amplification of pro-fibrotic mediators in the alcoholic lung. METHODS: To test this hypothesis, we analyzed tracheal epithelial cells and type II alveolar cells from control- or alcohol-fed rats, alcohol-treated mouse lung fibroblasts, and human bronchial epithelial cells in vitro for expression of various components of the IL-13 signaling pathway. Signaling via the IL-13 pathway was assessed by measuring levels of phosphorylated signal transducers and activators of transcription-6 (STAT6). In addition, we performed heterotopic tracheal transplantation using control-fed and alcohol-fed donor rats and analyzed tracheal allografts for expression of components of the IL-13 signaling pathway by RT-PCR and immunocytochemical analyses. RESULTS: Interleukin-13 expression was detected in type II alveolar epithelial cells and human bronchial epithelial cells, but not in lung fibroblasts. IL-13 expression was decreased in whole lung and type II cells in response to alcohol exposure. In all cell types analyzed, expression of IL-13 signaling receptor (IL-13R alpha(1)) mRNA was markedly increased. In contrast, mRNA and protein expression of the IL-13 decoy receptor (IL-13R alpha(2)) were decreased in all cells analyzed. Exposure to alcohol also increased STAT6 phosphorylation in response to IL-13 and lipopolysaccharide. CONCLUSIONS: Data from multiple cell types in the pulmonary system suggest that IL-13 and its receptors play a role in alcohol-mediated activation of pro-fibrotic pathways. Taken together, these data suggest that alcohol primes the airway for increased IL-13 signaling and subsequent tissue remodeling upon injury such as transplantation.