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A model of chronic lung allograft rejection in the rat


Jungraithmayr, W; Vogt, P; Inci, I; Hillinger, S; Arni, S; Passlick, B; Korom, S; Weder, W (2010). A model of chronic lung allograft rejection in the rat. European Respiratory Journal, 35(6):1354-1363.

Abstract

Bronchiolitis obliterans, the pathological hallmark of pulmonary chronic rejection, severely impacts long term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporary in vivo models. Here, we describe a model of chronic rejection with sensitized recipients receiving unilateral orthotopic rat lung transplants.LEW-rats, sensitized with BN-skin seven days before receiving left lung transplants from LBNF1-donors, were analyzed from day21 until day84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporine and characterized by histology, immunohistochemistry and RT-PCR.Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles with strong expression of alpha-SMA and upregulated mRNA for Th1-cytokines, alpha-SMA, TGF-beta and CCL5 but decreased gene expression for FOXP3.We describe a reproducible and clinically relevant experimental setup for progressive chronic rejection in rat pulmonary allografts. This model will allow for a better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as an in vivo setup for testing the efficacy of novel therapeutic interventions.

Bronchiolitis obliterans, the pathological hallmark of pulmonary chronic rejection, severely impacts long term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporary in vivo models. Here, we describe a model of chronic rejection with sensitized recipients receiving unilateral orthotopic rat lung transplants.LEW-rats, sensitized with BN-skin seven days before receiving left lung transplants from LBNF1-donors, were analyzed from day21 until day84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporine and characterized by histology, immunohistochemistry and RT-PCR.Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles with strong expression of alpha-SMA and upregulated mRNA for Th1-cytokines, alpha-SMA, TGF-beta and CCL5 but decreased gene expression for FOXP3.We describe a reproducible and clinically relevant experimental setup for progressive chronic rejection in rat pulmonary allografts. This model will allow for a better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as an in vivo setup for testing the efficacy of novel therapeutic interventions.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
04 Faculty of Medicine > University Hospital Zurich > Institute of Surgical Pathology
04 Faculty of Medicine > University Hospital Zurich > Division of Surgical Research
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:June 2010
Deposited On:04 Feb 2010 15:43
Last Modified:05 Apr 2016 13:51
Publisher:European Respiratory Society
ISSN:0903-1936
Publisher DOI:10.1183/09031936.00110609
PubMed ID:19840961
Permanent URL: http://doi.org/10.5167/uzh-29382

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