title: Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation.
abstract: Chronic lung allograft dysfunction (CLAD) remains the major obstacle to long-term survival following lung transplantation (LuTx). Morphologically CLAD is defined by obliterative remodelling of the small airways (bronchiolitis obliterans, BO) as well as a more recently described collagenous obliteration of alveoli with elastosis summarised as alveolar fibroelastosis (AFE). Both patterns are not restricted to pulmonary allografts, but have also been reported following haematopoietic stem cell transplantation (HSCT) and radio chemotherapy (RC). In this study we performed compartment-specific morphological and molecular analysis of BO and AFE lesions in human CLAD (n= 22), HSCT (n= 29) and RC (n= 6) lung explants, utilising conventional histopathology, laser-microdissection, PCR techniques and immunohistochemistry to assess fibrosis-associated gene and protein expression. Three key results emerged from our analysis of fibrosis-associated genes: (i) generally speaking, "BO is BO". Despite the varying clinical backgrounds, the molecular characteristics of BO lesions were found to be alike in all groups. (ii) "AFE is AFE". In all groups of patients suffering from restrictive changes to lung physiology due to AFE there were largely - but not absolutely - identical gene expression patterns. iii) BO concomitant to AFE after LuTx is characterised by an AFE-like molecular microenvironment, representing the only exception to (i). Additionally, we describe an evolutionary model for the AFE pattern: a non-specific fibrin-rich reaction to injury pattern triggers a misguided resolution attempt and eventual progression towards manifest AFE. Our data point towards an absence of classical fibrinolytic enzymes and an alternative fibrin degrading mechanism via macrophages, resulting in fibrous remodelling and restrictive functional changes. These data may serve as diagnostic adjuncts and help to predict the clinical course of respiratory dysfunction in LuTx and HSCT patients. Moreover, analysis of the mechanism of fibrinolysis and fibrogenesis may unveil potential therapeutic targets to alter the course of the eventually fatal lung remodelling.
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH)HanoverGermany; The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jonigk
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Berenice
authors.initials: B
authors.lastname: Rath
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Borchert
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Braubach
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Maegel
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Izykowski
authors.affiliation: The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany; Division of Cardiac, Thoracic, Transplantation and Vascular SurgeryMedical School HanoverHanoverGermany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Warnecke
authors.affiliation: The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany; Division of Cardiac, Thoracic, Transplantation and Vascular SurgeryMedical School HanoverHanoverGermany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sommer
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Kreipe
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Blach
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH) Hanover Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Anklamm
authors.affiliation: The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany; Division of Cardiac, Thoracic, Transplantation and Vascular SurgeryMedical School HanoverHanoverGermany.
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation Medical School Hanover Hanover Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation Medical School Hanover Hanover Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stadler
authors.affiliation: The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany; Department of Respiratory Medicine, Medical School Hanover, Hanover, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.affiliation: The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany; Department of Respiratory Medicine, Medical School Hanover, Hanover, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Gottlieb
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH)HanoverGermany; The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany.
authors.forename: Mark
authors.initials: M
authors.lastname: Kuehnel
authors.affiliation: Institute of Pathology, Hannover Medical School (MHH)HanoverGermany; The German Center for Lung Research (Deutsches Zentrum für Lungenforschung DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hanover (BREATH)HanoverGermany.
authors.forename: Florian
authors.initials: F
authors.lastname: Laenger
keywords: allograft; bronchiolitis obliterans/physiopathology; hematopoietic stem cell transplantation/adverse effects; idiopathic pulmonary fibrosis/pathology; lung transplantation/adverse effects; primary graft dysfunction/physiopathology; pulmonary fibrosis/pathology