Spectrum of chronic lung allograft pathology in a mouse minor‐mismatched orthotopic lung transplant model

Chronic lung allograft dysfunction ( CLAD ) is a fatal condition that limits survival after lung transplantation ( LT x). The pathological hallmark of CLAD is obliterative bronchiolitis ( OB ). A subset of patients present with a more aggressive CLAD phenotype, called restrictive allograft syndrome ( RAS ), characterized by lung parenchymal fibrosis ( PF ). The mouse orthotopic single LT x model has proven relevant to the mechanistic study of allograft injury. The minor‐alloantigen‐mismatched strain combination using C57 BL /10(B10) donors and C57 BL /6(B6) recipients reportedly leads to OB . Recognizing that OB severity is a spectrum that may coexist with other pathologies, including PF , we aimed to characterize and quantify pathologic features of CLAD in this model. Left LT x was performed in the following combinations: B10→B6, B6→B10, B6→B6. Four weeks posttransplant, blinded pathologic semi‐quantitative assessment showed that OB was present in 66% of B10→B6 and 30% of B6→B10 grafts. Most mice with OB also had PF with a pattern of pleuroparenchymal fibroelastosis, reminiscent of human RAS ‐related pathology. Grading of pathologic changes demonstrated variable severity of airway fibrosis, PF , acute rejection, vascular fibrosis, and epithelial changes, similar to those seen in human CLAD . These assessments can make the murine LT x model a more useful tool for further mechanistic studies of CLAD pathogenesis.