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-and TGF-1 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. Author's contributionsYY contributed to the experimental surgeries and retrieved and analyzed the data and codrafted the manuscript (MS); KK and LD analyzed the data; DK retrieved and analyzed the data; JJH contributed to the data analysis; II co-drafted the MS; AB contributed the data analysis and codrafted the MS; TM contributed the data analyses; WW codrafted the MS; WJ designed and coordinated the study and wrote the MS. All authors read and approved the final manuscript. DisclosureThe authors declare no conflicts of interest. FundingNone A C C E P T E D 4 AbstractBackground: Several mouse lung transplantation (Tx) models have been proposed for the study of
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 re-producibility. 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 histocompati-bility 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-ï¿¿ and TGF-ï¿¿1 were higher, and IL-10 was lower in the MAJOR group. Im-munohistochemistry 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. Wolfgang (2018). Chronic airway fibrosis in orthotopic mouse lung transplantation models: an experimental reappraisal. Transplantation, 102(2):e49-e58.
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-and TGF-1 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. Author's contributionsYY contributed to the experimental surgeries and retrieved and analyzed the data and codrafted the manuscript (MS); KK and LD analyzed the data; DK retrieved and analyzed the data; JJH contributed to the data analysis; II co-drafted the MS; AB contributed the data analysis and codrafted the MS; TM contributed the data analyses; WW codrafted the MS; WJ designed and coordinated the study and wrote the MS. All authors read and approved the final manuscript. DisclosureThe authors declare no conflicts of interest. FundingNone A C C E P T E D 4 AbstractBackground: Several mouse lung transplantation (Tx) models have been proposed for the study of
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