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Artikel ; Online: Mesenchymal Stromal Cell Therapy in Lung Transplantation

Antti I. Nykänen / Mingyao Liu / Shaf Keshavjee

Bioengineering, Vol 10, Iss 728, p

2023 Band 728

Abstract: Lung transplantation is often the only viable treatment option for a patient with end-stage lung disease. Lung transplant results have improved substantially over time, but ischemia-reperfusion injury, primary graft dysfunction, acute rejection, and ... ...

Abstract	Lung transplantation is often the only viable treatment option for a patient with end-stage lung disease. Lung transplant results have improved substantially over time, but ischemia-reperfusion injury, primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction (CLAD) continue to be significant problems. Mesenchymal stromal cells (MSC) are pluripotent cells that have anti-inflammatory and protective paracrine effects and may be beneficial in solid organ transplantation. Here, we review the experimental studies where MSCs have been used to protect the donor lung against ischemia-reperfusion injury and alloimmune responses, as well as the experimental and clinical studies using MSCs to prevent or treat CLAD. In addition, we outline ex vivo lung perfusion (EVLP) as an optimal platform for donor lung MSC delivery, as well as how the therapeutic potential of MSCs could be further leveraged with genetic engineering.
Schlagwörter	mesenchymal stromal cell ; lung transplantation ; cell therapy ; gene therapy ; ex vivo lung perfusion ; Technology ; T ; Biology (General) ; QH301-705.5
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2023-06-01T00:00:00Z
Verlag	MDPI AG
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Robust segregation of donor and recipient cells from single-cell RNA-sequencing of transplant samples

Gavin W. Wilson / Allen Duong / Sajad Moshkelgosha / Gary Bader / Shaf Keshavjee / Tereza Martinu / Stephen C. Juvet / Jonathan C. Yeung

Frontiers in Transplantation, Vol

2023 Band 2

Abstract: BackgroundSingle-cell RNA-sequencing (scRNA-seq) technology has revealed novel cell populations in organs, uncovered regulatory relationships between genes, and allowed for tracking of cell lineage trajectory during development. It demonstrates promise ... ...

Abstract	BackgroundSingle-cell RNA-sequencing (scRNA-seq) technology has revealed novel cell populations in organs, uncovered regulatory relationships between genes, and allowed for tracking of cell lineage trajectory during development. It demonstrates promise as a method to better understand transplant biology; however, fundamental bioinformatic tools for its use in the context of transplantation have not been developed. One major need has been a robust method to identify cells as being either donor or recipient genotype origin, and ideally without the need to separately sequence the donor and recipient.MethodsWe implemented a novel two-stage genotype discovery method (scTx) optimized for transplant samples by being robust to disparities in cell number and cell type. Using both in silico and real-world scRNA-seq transplant data, we benchmarked our method against existing demultiplexing methods to profile their limitations in terms of sequencing depth, donor and recipient cell imbalance, and single nucleotide variant input selection.ResultsUsing in silico data, scTx could more accurately separate donor from recipient cells and at much lower genotype ratios than existing methods. This was further validated using solid-organ scRNA-seq data where scTx could more reliably identify when a second genotype was present and at lower numbers of cells from a second genotype.ConclusionscTx introduces the capability to accurately segregate donor and recipient gene expression at the single-cell level from scRNA-seq data without the need to separately genotype the donor and recipient. This will facilitate the use of scRNA-seq in the context of transplantation.
Schlagwörter	single-cell RNA-sequencing ; solid-organ transplantation ; bioinformatics ; application ; donor and recipient genotypes ; Specialties of internal medicine ; RC581-951
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2023-06-01T00:00:00Z
Verlag	Frontiers Media S.A.
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Donor IL-17 receptor A regulates LPS-potentiated acute and chronic murine lung allograft rejection

Tatsuaki Watanabe / Stephen C. Juvet / Gregory Berra / Jan Havlin / Wenshan Zhong / Kristen Boonstra / Tina Daigneault / Miho Horie / Chihiro Konoeda / Grace Teskey / Zehong Guan / David M. Hwang / Mingyao Liu / Shaf Keshavjee / Tereza Martinu

JCI Insight, Vol 8, Iss

2023 Band 21

Abstract: Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL- ...

Abstract	Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.
Schlagwörter	Pulmonology ; Transplantation ; Medicine ; R
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2023-11-01T00:00:00Z
Verlag	American Society for Clinical investigation
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Oesophageal stasis is a risk factor for chronic lung allograft dysfunction and allograft failure in lung transplant recipients

Rayoun Ramendra / Juan C. Fernández-Castillo / Ella Huszti / Rasheed Ghany / Meghan Aversa / Jan Havlin / Peter Riddell / Cecilia M. Chaparro / Lianne G. Singer / Louis Liu / Shaf Keshavjee / Jonathan C. Yeung / Tereza Martinu

ERJ Open Research, Vol 9, Iss

2023 Band 5

Abstract: Background Morbidity and mortality in lung transplant recipients are often triggered by recurrent aspiration events, potentiated by oesophageal and gastric disorders. Previous small studies have shown conflicting associations between oesophageal function ...

Abstract	Background Morbidity and mortality in lung transplant recipients are often triggered by recurrent aspiration events, potentiated by oesophageal and gastric disorders. Previous small studies have shown conflicting associations between oesophageal function and the development of chronic lung allograft dysfunction (CLAD). Herein, we sought to investigate the relationship between oesophageal motility disorders and long-term outcomes in a large retrospective cohort of lung transplant recipients. Methods All lung transplant recipients at the Toronto Lung Transplant Program from 2012 to 2018 with available oesophageal manometry testing within the first 7 months post-transplant were included in this study. Patients were categorised according to the Chicago Classification of oesophageal disorders (v3.0). Associations between oesophageal motility disorders with the development of CLAD and allograft failure (defined as death or re-transplantation) were assessed. Results Of 487 patients, 57 (12%) had oesophagogastric junction outflow obstruction (OGJOO) and 47 (10%) had a disorder of peristalsis (eight major, 39 minor). In a multivariable analysis, OGJOO was associated with an increased risk of CLAD (HR 1.71, 95% CI 1.15–2.55, p=0.008) and allograft failure (HR 1.69, 95% CI 1.13–2.53, p=0.01). Major disorders of peristalsis were associated with an increased risk of CLAD (HR 1.55, 95% CI 1.01–2.37, p=0.04) and allograft failure (HR 3.33, 95% CI 1.53–7.25, p=0.002). Minor disorders of peristalsis were not significantly associated with CLAD or allograft failure. Conclusion Lung transplant recipients with oesophageal stasis characterised by OGJOO or major disorders of peristalsis were at an increased risk of adverse long-term outcomes. These findings will help with risk stratification of lung transplant recipients and personalisation of treatment for aspiration prevention.
Schlagwörter	Medicine ; R
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2023-09-01T00:00:00Z
Verlag	European Respiratory Society
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Evaluation of a decellularized bronchial patch transplant in a porcine model

Daisuke Taniguchi / Satoshi Kamata / Sara Rostami / Stephen Tuin / Alba Marin-Araujo / Kelly Guthrie / Thomas Petersen / Thomas K. Waddell / Golnaz Karoubi / Shaf Keshavjee / Siba Haykal

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Band 11

Abstract: Abstract Biological scaffolds for airway reconstruction are an important clinical need and have been extensively investigated experimentally and clinically, but without uniform success. In this study, we evaluated the use of a decellularized bronchus ... ...

Abstract	Abstract Biological scaffolds for airway reconstruction are an important clinical need and have been extensively investigated experimentally and clinically, but without uniform success. In this study, we evaluated the use of a decellularized bronchus graft for airway reconstruction. Decellularized left bronchi were procured from decellularized porcine lungs and utilized as grafts for airway patch transplantation. A tracheal window was created and the decellularized bronchus was transplanted into the defect in a porcine model. Animals were euthanized at 7 days, 1 month, and 2 months post-operatively. Histological analysis, immunohistochemistry, scanning electron microscopy, and strength tests were conducted in order to evaluate epithelialization, inflammation, and physical strength of the graft. All pigs recovered from general anesthesia and survived without airway obstruction until the planned euthanasia timepoint. Histological and electron microscopy analyses revealed that the decellularized bronchus graft was well integrated with native tissue and covered by an epithelial layer at 1 month. Immunostaining of the decellularized bronchus graft was positive for CD31 and no difference was observed with immune markers (CD3, CD11b, myeloperoxidase) at two months. Although not significant, tensile strength was decreased after one month, but recovered by two months. Decellularized bronchial grafts show promising results for airway patch reconstruction in a porcine model. Revascularization and re-epithelialization were observed and the immunological reaction was comparable with the autografts. This approach is clinically relevant and could potentially be utilized for future applications for tracheal replacement.
Schlagwörter	Medicine ; R ; Science ; Q
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2023-12-01T00:00:00Z
Verlag	Nature Portfolio
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Telerehabilitation for Lung Transplant Candidates and Recipients During the COVID-19 Pandemic

Lisa Wickerson / Denise Helm / Chaya Gottesman / Dmitry Rozenberg / Lianne G Singer / Shaf Keshavjee / Aman Sidhu

JMIR mHealth and uHealth, Vol 9, Iss 6, p e

Program Evaluation

2021 Band 28708

Abstract: BackgroundThe COVID-19 pandemic resulted in a rapid shift from center-based rehabilitation to telerehabilitation for chronic respiratory disease and lung transplantation due to infection control precautions. Clinical experience with this delivery model ... ...

Abstract	BackgroundThe COVID-19 pandemic resulted in a rapid shift from center-based rehabilitation to telerehabilitation for chronic respiratory disease and lung transplantation due to infection control precautions. Clinical experience with this delivery model on a large scale has not been described. ObjectiveThe aim of this study is to describe usage and satisfaction of providers and lung transplant (LTx) candidates and recipients and functional outcomes following the broad implementation of telerehabilitation with remote patient monitoring during the first wave of the COVID-19 pandemic. MethodsThis study was a program evaluation of providers, LTx candidates, and early LTx recipients who used a web-based, remote monitoring app for at least four weeks between March 16 and September 1, 2020, to participate in telerehabilitation. Within-subjects analysis was performed for physical activity, Self-efficacy For Exercise (SEE) scale score, aerobic and resistance exercise volumes, 6-minute walk test results, and Short Physical Performance Battery (SPPB) results. ResultsIn total, 78 LTx candidates and 33 recipients were included (57 [51%] males, mean age 58 [SD 12] years, 58 [52%] with interstitial lung disease, 34 [31%] with chronic obstructive pulmonary disease). A total of 50 (64%) LTx candidates and 17 (51%) LTx recipients entered ≥10 prescribed exercise sessions into the app during the study time frame. In addition, 35/42 (83%) candidates agreed the app helped prepare them for surgery and 18/21 (85%) recipients found the app helpful in their self-recovery. The strongest barrier perceived by physiotherapists delivering the telerehabilitation was patient access to home exercise and monitoring equipment. Between the time of app registration and ≥4 weeks on the waiting list, 26 LTx candidates used a treadmill, with sessions increasing in mean duration (from 16 to 22 minutes, P=.002) but not speed (from 1.7 to 1.75 mph, P=.31). Quadriceps weight (pounds) for leg extension did not change (median 3.5, IQR 2.4-5 versus median 4.3, ...
Schlagwörter	Information technology ; T58.5-58.64 ; Public aspects of medicine ; RA1-1270
Thema/Rubrik (Code)	796
Sprache	Englisch
Erscheinungsdatum	2021-06-01T00:00:00Z
Verlag	JMIR Publications
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Thrombopoietin participates in platelet activation in COVID-19 patients

Enrico Lupia / Marialessia Capuano / Barbara Vizio / Martina Schiavello / Ornella Bosco / Maria Gelardi / Edoardo Favale / Emanuele Pivetta / Fulvio Morello / Shahid Husain / Shaf Keshavjee / Lorenzo Del Sorbo / Giuseppe Montrucchio

EBioMedicine, Vol 85, Iss , Pp 104305- (2022)

2022

Abstract: Summary: Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is characterized by enhanced platelet activation and diffuse hemostatic alterations, which may contribute to immunothrombosis/thromboinflammation and subsequent development of ... ...

Abstract	Summary: Background: The pathogenesis of coronavirus disease 2019 (COVID-19) is characterized by enhanced platelet activation and diffuse hemostatic alterations, which may contribute to immunothrombosis/thromboinflammation and subsequent development of target-organ damage.Thrombopoietin (THPO), a growth factor essential to megakariocyte proliferation, is known to prime platelet activation and leukocyte-platelet interaction. In addition, THPO concentrations increase in several critical diseases, such as acute cardiac ischemia and sepsis, thus representing a potential diagnostic and prognostic biomarker. Furthermore, several data suggest that interleukin (IL)-6 is one of the most important inflammatory mediators involved in these phenomena, which led to explore the potential therapeutic role of IL-6 inhibitors.In this prospective cohort study, we aimed to study THPO and IL-6 concentrations in COVID-19 patients at the time of first clinical evaluation in the Emergency Department (ED), and to investigate their potential use as diagnostic and prognostic biomarkers. In addition, we sought to explore the role of THPO contained in plasma samples obtained from COVID-19 patients in priming in vitro platelet activation and leukocyte-platelet interaction. Methods: We enrolled 66 patients presenting to the ED with symptoms suggestive of COVID-19, including 47 with confirmed COVID-19 and 19 in whom COVID-19 was excluded (Non-COVID-19 patients). As controls, we also recruited 18 healthy subjects.In vitro, we reproduced the effects of increased circulating THPO on platelet function by adding plasma from COVID-19 patients or controls to platelet-rich plasma or whole blood obtained by healthy donors, and we indirectly studied the effect of THPO on platelet activation by blocking its biological activity. Findings: THPO levels were higher in COVID-19 patients than in both Non-COVID-19 patients and healthy subjects. Studying THPO as diagnostic marker for the diagnosis of COVID-19 by receiver-operating-characteristic (ROC) ...
Schlagwörter	COVID-19 ; Thrombopoietin ; Interleukin-6 ; Platelet activation ; Biomarker ; Thromboinflammation ; Medicine ; R ; Medicine (General) ; R5-920
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2022-11-01T00:00:00Z
Verlag	Elsevier
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Successful 3-day lung preservation using a cyclic normothermic ex vivo lung perfusion strategy

Aadil Ali / Antti I. Nykanen / Erika Beroncal / Edson Brambate / Andrea Mariscal / Vinicius Michaelsen / Aizhou Wang / Mitsuaki Kawashima / Rafaela V.P. Ribeiro / Yu Zhang / Eddy Fan / Laurent Brochard / Jonathan Yeung / Tom Waddell / Mingyao Liu / Ana C. Andreazza / Shaf Keshavjee / Marcelo Cypel

EBioMedicine, Vol 83, Iss , Pp 104210- (2022)

2022

Abstract: Summary: Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo ... ...

Abstract	Summary: Background: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular “recharge”, allowing for multi-day lung preservation. Methods: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. Findings: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. Interpretation: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. Funding: This work was supported by the UHN Foundation (Grant#1013612).
Schlagwörter	Ex vivo lung perfusion ; Lung preservation ; Lung transplant ; Metabolomics ; Medicine ; R ; Medicine (General) ; R5-920
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2022-09-01T00:00:00Z
Verlag	Elsevier
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: A novel pre-clinical strategy to deliver antimicrobial doses of inhaled nitric oxide.

Vinicius S Michaelsen / Rafaela V P Ribeiro / Edson Brambate / Aadil Ali / Aizhou Wang / Layla Pires / Mitsuaki Kawashima / Yu Zhang / Anajara Gazzalle / Shaf Keshavjee / Lorenzo Del Sorbo / Marcelo Cypel

PLoS ONE, Vol 16, Iss 10, p e

2021 Band 0258368

Abstract: Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. ... ...

Abstract	Effective treatment of respiratory infections continues to be a major challenge. In high doses (≥160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent, including its efficacy in vitro for coronavirus family. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied. Herein we aim to explore the feasibility and safety of delivering continuous high-dose iNO over an extended period of time using an in vivo animal model. Yorkshire pigs were randomized to one of the following two groups: group 1, standard ventilation; and group 2, standard ventilation + continuous iNO 160 ppm + methylene blue (MB) as intravenous bolus, whenever required, to maintain metHb <6%. Both groups were ventilated continuously for 6 hours, then the animals were weaned from sedation, mechanical ventilation and followed for 3 days. During treatment, and on the third post-operative day, physiologic assessments were performed to monitor lung function and other significative markers were assessed for potential pulmonary or systemic injury. No significant change in lung function, or inflammatory markers were observed during the study period. Both gas exchange function, lung tissue cytokine analysis and histology were similar between treated and control animals. During treatment, levels of metHb were maintained <6% by administration of MB, and NO2 remained <5 ppm. Additionally, considering extrapulmonary effects, no significant changes were observed in biochemistry markers. Our findings showed that high-dose iNO delivered continuously over 6 hours with adjuvant MB is clinically feasible and safe. These findings support the development of investigations of continuous high-dose iNO treatment of respiratory tract infections, including SARS-CoV-2.
Schlagwörter	Medicine ; R ; Science ; Q
Thema/Rubrik (Code)	610 ; 630
Sprache	Englisch
Erscheinungsdatum	2021-01-01T00:00:00Z
Verlag	Public Library of Science (PLoS)
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Chronic Candida dubliniensis meningitis in a lung transplant recipient

Sabina Herrera / Paolo Pavone / Deepali Kumar / Lianne Singer / Atul Humar / Cecilia Chaparro / Shaf Keshavjee / Shahid Husain / Coleman Rotstein

Medical Mycology Case Reports, Vol 24, Iss , Pp 41-

2019 Band 43

Abstract: Candida spp. are common colonizers of the oral mucosa and respiratory tract in lung transplant recipients. Although thought to be non-pathogenic in most cases, donor derived infections related to Candida spp. have been described. Among the manifestations ...

Abstract	Candida spp. are common colonizers of the oral mucosa and respiratory tract in lung transplant recipients. Although thought to be non-pathogenic in most cases, donor derived infections related to Candida spp. have been described. Among the manifestations of invasive candidiasis, chronic meningitis is one of the rarest and one of the most challenging to diagnose, due to the indolence of the disease and the low yield of the CSF cultures. It is associated with severe morbidity and a high mortality. Fungal PCR and BD glucan assays can be assistance in its diagnosis, although these tests are not widely available. We report a case of a possible donor derived Candida dubliniensis infection in a lung transplant recipient, who initially presented with empyema that was treated successfully, but subsequently developed chronic meningitis. Diagnosis was delayed due to the low yield of CSF cultures, and was confirmed with fungal PCR and BD glucan assay. Keywords: Candida meningitis, Chronic meningitis, Candida dubliniensis, Lung transplant, Immunocompromised
Schlagwörter	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2019-06-01T00:00:00Z
Verlag	Elsevier
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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