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Chronic airway fibrosis in orthotopic mouse lung transplantation models: an experimental reappraisal


Yamada, Yoshito; Windirsch, Kevin; Dubs, Linus; Kenkel, David; Jang, Jae-Hwi; Inci, Ilhan; Boss, Andreas; Martinu, Tereza; Vanaudenaerde, Bart M; Weder, Walter; Jungraithmayr, Wolfgang (2017). Chronic airway fibrosis in orthotopic mouse lung transplantation models: an experimental reappraisal. Transplantation:Epub ahead of print.

Abstract

BACKGROUND: Several mouse lung transplantation (Tx) models have been proposed for the study of chronic airway fibrosis (CAF), the most prevalent complication seen in human lung transplant recipients, termed chronic lung allograft dysfunction (CLAD). Alternatively, it has been called for to establish an experimental animal model for restrictive allograft syndrome (RAS), another phenotype of CLAD. However, these mouse transplant models exhibit significant heterogeneity in consistency and reproducibility. We therefore aimed at reevaluating current available models.
METHODS: 4 different Tx combinations were employed that manifest CAF: 2 minor antigen-mismatched Tx combinations (MINOR, donor: C57BL/10, recipient: C57BL/6J); or MINOR-N using recipient C57BL/6N, major histocompatibility antigen-mismatched immunosuppressed Tx (MAJOR, donor: BALB/c, recipient: C57BL/6J) and syngeneic Tx (SYN, donor and recipient: C57BL/6J) as control. The recipients were harvested and analyzed at week 8. Oxygenation, histology, reverse transcription polymerase chain reaction (RT-PCR), and magnetic resonance imaging were performed to analyze outcome of those models.
RESULTS: The most prominent manifestation of CAF, thickest subepithelial fibrotic changes, worst oxygenation and the most severe acute rejection were detected in the MAJOR group, compared to all other (p<0.05). Gene expressions of TNF-α and TGF-β1 were higher, and IL-10 was lower in the MAJOR group. Immunohistochemistry found pleuroparenchymal fibrotic change in both the MAJOR and MINOR-J group.
CONCLUSIONS: We propose the major mismatch model under mild immunosuppression as the most suitable model for studying posttransplant CAF, and both the major and minor mismatch models for the restrictive phenotype.

Abstract

BACKGROUND: Several mouse lung transplantation (Tx) models have been proposed for the study of chronic airway fibrosis (CAF), the most prevalent complication seen in human lung transplant recipients, termed chronic lung allograft dysfunction (CLAD). Alternatively, it has been called for to establish an experimental animal model for restrictive allograft syndrome (RAS), another phenotype of CLAD. However, these mouse transplant models exhibit significant heterogeneity in consistency and reproducibility. We therefore aimed at reevaluating current available models.
METHODS: 4 different Tx combinations were employed that manifest CAF: 2 minor antigen-mismatched Tx combinations (MINOR, donor: C57BL/10, recipient: C57BL/6J); or MINOR-N using recipient C57BL/6N, major histocompatibility antigen-mismatched immunosuppressed Tx (MAJOR, donor: BALB/c, recipient: C57BL/6J) and syngeneic Tx (SYN, donor and recipient: C57BL/6J) as control. The recipients were harvested and analyzed at week 8. Oxygenation, histology, reverse transcription polymerase chain reaction (RT-PCR), and magnetic resonance imaging were performed to analyze outcome of those models.
RESULTS: The most prominent manifestation of CAF, thickest subepithelial fibrotic changes, worst oxygenation and the most severe acute rejection were detected in the MAJOR group, compared to all other (p<0.05). Gene expressions of TNF-α and TGF-β1 were higher, and IL-10 was lower in the MAJOR group. Immunohistochemistry found pleuroparenchymal fibrotic change in both the MAJOR and MINOR-J group.
CONCLUSIONS: We propose the major mismatch model under mild immunosuppression as the most suitable model for studying posttransplant CAF, and both the major and minor mismatch models for the restrictive phenotype.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Diagnostic and Interventional Radiology
Dewey Decimal Classification:610 Medicine & health
Date:18 August 2017
Deposited On:19 Sep 2017 15:48
Last Modified:19 Sep 2017 15:55
Publisher:Lippincott Williams & Wilkins
ISSN:0041-1337
Additional Information:This is a non-final version of an article published in final form in Transplantation. Publish Ahead of Print, AUG 2017, Yoshito Yamada; Kevin Windirsch; and 9 more. DOI: 10.1097/TP.0000000000001917
Publisher DOI:https://doi.org/10.1097/TP.0000000000001917
PubMed ID:28825953

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