title: Normothermic Ex Vivo Lung Perfusion in Brain-dead Donors Reduces Inflammatory Cytokines and Toll-like Receptor Expression.
abstract: Inflammatory responses and innate immunologic reactions play an important role in the respiratory system. Ex vivo lung perfusion (EVLP) is considered a novel method in the evaluation and reconditioning of donor lungs prior to transplantation. However, EVLP's effect on inflammatory and metabolic markers of human lung tissue is unknown.  This study investigated how the performance of EVLP on brain-dead (BD) donor lungs affects the production and release of inflammatory cytokines (IL-6, IL-8, and TNF-a), inflammatory cells and toll-like receptors (TLR) -2, 4. This study was conducted with an animal subject for qualification of EVLP team and then EVLP was performed on 4 human cases referred to Masih Daneshvari Hospital (Tehran,Iran), from May 2013 to July 2015. Two of these cases, who had acceptable lung function parameters, were enrolled in this study for immunologic investigations. Bronchoalveolar lavages (BAL) were taken before and after EVLP. Cytokines were quantitatively measured before lung retrieval, at the end of the lung removal, at the start of EVLP, and at the end of the each hour of EVLP. TLR expression was measured on the cells obtained by flow cytometry. TNF-a, IL-6 and IL-8 decreased in each stage of washing perfusate in both cases, and the level of cytokines in serum was in the normal range. Flow cytometry analysis revealed a decreasing expression of CD3, CD4/8, CD19, and CD16+56, as well as TLR-2 and TLR-4 in both cases. Intra-capillary pools of pro-inflammatory cytokines (IL-6, IL-8, and TNF-a) were determined to contribute to the lung injury during prolonged lung perfusion. This raises the possibility that EVLP donor lungs could be less immunogenic than standard lungs. However, to assess EVLP's effects on lung grafts and optimize recipient outcomes, further studies with a sufficient number of lungs are required.
authors.affiliation: Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Shadi
authors.initials: S
authors.lastname: Shafaghi
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, Netherlands AND Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Mortaz
authors.affiliation: Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Azizollah
authors.initials: A
authors.lastname: Abbasi Dezfuli
authors.affiliation: Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hoda
authors.initials: H
authors.lastname: Godarzi
authors.affiliation: Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Sheikhy
authors.affiliation: Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Ansari Aval
authors.affiliation: Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Behrooz
authors.initials: B
authors.lastname: Farzanegan
authors.affiliation: Tobacco Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Habib
authors.initials: H
authors.lastname: Emami
authors.affiliation: Minimally Invasive Surgery Research Center (MISRC), Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Fatemeh Sadat
authors.initials: FS
authors.lastname: Hosseini-Baharanchi
authors.affiliation: Lung Transplant Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran AND Directors of Organ Transplantation and Special Diseases Office, Ministry of Health and Medical Education, Tehran, Iran.
authors.forename: Katayoun
authors.initials: K
authors.lastname: Najafizadeh
mesh_terms: D001926:Brain Death; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008168:Lung / Q000276:immunology*; D016040:Lung Transplantation; D008297:Male; D010477:Perfusion; D014019:Tissue Donors; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D016207:Cytokines; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
keywords: Cytokines; Ex vivo lung perfusion (EVLP); Lung transplantation; TLR; TNF-a