Alpha 1 Antitrypsin Treatment during Human Ex Vivo Lung Perfusion Improves Lung Function by Protecting Lung Endothelium

Mariscal, A.; Nykänen, Antti; Tikkanen, Jussi; Ali, Aiman; Soltanieh, Sahar; Duong, A.; Galasso, M.; Juvet, S.; Martinu, T.; Cypel, Marcelo; Liu, M.; Keshavjee, S.

doi:10.1016/j.healun.2020.01.1282

Cited by 7 publications

(5 citation statements)

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“…First, BEAS-2B cells were derived from bronchial epithelial cells and therefore may not fully represent alveolar epithelial cells; however, this is the only non-cancer human lung cell line currently available. On the other hand, as presented in the Introduction Section, BEAS-2B cells have been successfully used for mechanistic studies and drug testing under the simulated IR conditions, and results have been validated in vivo with animal models or damaged human donor lungs declined from clinical transplant program [8][9][10][11][12][13]15,16]. Both BEAS-2B and HPMEC cells are immortalized cell lines.…”

Section: Limitations Of the Studymentioning

confidence: 99%

“…Ex vivo lung perfusion (EVLP) is a new technology for donor lung assessment and repair [14]. During EVLP, A1AT reduced IRI in pig lungs [15] and repaired severely damaged human donor lungs declined by the clinical transplant program [16]. This series of studies presented a drug discovery pipeline to translate from basic scientific research to clinical application [17] and to support the cell culture model as a useful tool for initial drug screening and exploration of underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Ischemia-Reperfusion Injury in a Simulated Lung Transplant Setting Differentially Regulates Transcriptomic Profiles between Human Lung Endothelial and Epithelial Cells

Saren

Wong

et al. 2021

Cells

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Current understanding of mechanisms of ischemia-reperfusion-induced lung injury during lung preservation and transplantation is mainly based on clinical observations and animal studies. Herein, we used cell and systems biology approaches to explore these mechanisms at transcriptomics levels, especially by focusing on the differences between human lung endothelial and epithelial cells, which are crucial for maintaining essential lung structure and function. Human pulmonary microvascular endothelial cells and human lung epithelial cells were cultured to confluent, subjected to different cold ischemic times (CIT) to mimic static cold storage with preservation solution, and then subjected to warm reperfusion with a serum containing culture medium to simulate lung transplantation. Cell morphology, viability, and transcriptomic profiles were studied. Ischemia-reperfusion injury induced a CIT time-dependent cell death, which was associated with dramatic changes in gene expression. Under normal control conditions, endothelial cells showed gene clusters enriched in the vascular process and inflammation, while epithelial cells showed gene clusters enriched in protein biosynthesis and metabolism. CIT 6 h alone or after reperfusion had little effect on these phenotypic characteristics. After CIT 18 h, protein-biosynthesis-related gene clusters disappeared in epithelial cells; after reperfusion, metabolism-related gene clusters in epithelial cells and multiple gene clusters in the endothelial cells also disappeared. Human pulmonary endothelial and epithelial cells have distinct phenotypic transcriptomic signatures. Severe cellular injury reduces these gene expression signatures in a cell-type-dependent manner. Therapeutics that preserve these transcriptomic signatures may represent new treatment to prevent acute lung injury during lung transplantation.

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Section: Limitations Of the Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ischemia-Reperfusion Injury in a Simulated Lung Transplant Setting Differentially Regulates Transcriptomic Profiles between Human Lung Endothelial and Epithelial Cells

Saren

Wong

et al. 2021

Cells

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“…There is evidence from ex-situ perfusion of animal and discarded human lungs that SPIs may decrease systemic and tissue inflammation, improve ex-situ protection of the lungs, and attenuate tissue edema (222,223). The anti-inflammatory and tissue protecting effects of SPIs has been assessed in the context of ESHP to protect the myocardium from IRI, and have shown cardioprotective effects against it (224,225), but not in attenuation of the inflammatory and oxidative stress responses related to ECC specifically.…”

Section: Serine Protease Inhibitorsmentioning

confidence: 99%

Inflammation and Oxidative Stress in the Context of Extracorporeal Cardiac and Pulmonary Support

2022

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Extracorporeal circulation (ECC) systems, including cardiopulmonary bypass, and extracorporeal membrane oxygenation have been an irreplaceable part of the cardiothoracic surgeries, and treatment of critically ill patients with respiratory and/or cardiac failure for more than half a century. During the recent decades, the concept of extracorporeal circulation has been extended to isolated machine perfusion of the donor organ including thoracic organs (ex-situ organ perfusion, ESOP) as a method for dynamic, semi-physiologic preservation, and potential improvement of the donor organs. The extracorporeal life support systems (ECLS) have been lifesaving and facilitating complex cardiothoracic surgeries, and the ESOP technology has the potential to increase the number of the transplantable donor organs, and to improve the outcomes of transplantation. However, these artificial circulation systems in general have been associated with activation of the inflammatory and oxidative stress responses in patients and/or in the exposed tissues and organs. The activation of these responses can negatively affect patient outcomes in ECLS, and may as well jeopardize the reliability of the organ viability assessment, and the outcomes of thoracic organ preservation and transplantation in ESOP. Both ECLS and ESOP consist of artificial circuit materials and components, which play a key role in the induction of these responses. However, while ECLS can lead to systemic inflammatory and oxidative stress responses negatively affecting various organs/systems of the body, in ESOP, the absence of the organs that play an important role in oxidant scavenging/antioxidative replenishment of the body, such as liver, may make the perfused organ more susceptible to inflammation and oxidative stress during extracorporeal circulation. In the present manuscript, we will review the activation of the inflammatory and oxidative stress responses during ECLP and ESOP, mechanisms involved, clinical implications, and the interventions for attenuating these responses in ECC.

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“…compliance (53). Recently, the Kyoto group demonstrated that high dose procaterol inhalation during EVLP improved graft function using a canine DCD model (54).…”

Section: Surfactantmentioning

confidence: 99%

“…EVLP as a platform for specific treatments(13)(14)(15)(16)37,(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67) the higher possibility of PGD(72). Several attempts have been made to repair lungs with aspiration injury…”

mentioning

confidence: 99%

Ex vivo lung perfusion

Watanabe¹,

Cypel²,

Keshavjee³

2021

J Thorac Dis

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Alpha 1 Antitrypsin Treatment during Human Ex Vivo Lung Perfusion Improves Lung Function by Protecting Lung Endothelium

Cited by 7 publications

References 0 publications

Ischemia-Reperfusion Injury in a Simulated Lung Transplant Setting Differentially Regulates Transcriptomic Profiles between Human Lung Endothelial and Epithelial Cells

Ischemia-Reperfusion Injury in a Simulated Lung Transplant Setting Differentially Regulates Transcriptomic Profiles between Human Lung Endothelial and Epithelial Cells

Inflammation and Oxidative Stress in the Context of Extracorporeal Cardiac and Pulmonary Support

Ex vivo lung perfusion

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