Similar molecular subtypes of lung injury patterns in interstitial lung disease, stem cell and lung transplantation
23.Februar 2017 (online)
Obliteration of bronchioles of the lung (BO) as well as collagenous obliteration of alveoli with elastosis summarized as alveolar fibroelastosis (AFE) are injury patterns of the lung observed in chronic lung allograft dysfunction (CLAD), following lung transplantation (LuTx) as well as after hematopoetic stem cell transplantation (HSCT), combined radio-chemotherapy and in subforms of interstitial lung disease. Regardless of the clinical background both injury patterns are associated with a high mortality.
Utilizing conventional histopathology, laser-microdissection, PCR/hybridization techniques, immunohistochemistry and 3-D reconstruction techniques we performed compartment-specific morphological and molecular analyses of BO and AFE lesions in human lung explants to assess underlying molecular mechanisms.
Three key results emerged from our analysis 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 characterized by an AFE-like molecular microenvironment, representing the only exception to i).
Additionally, we describe a shared evolutionary model for the AFE pattern, independent of the clinical setting for the first time: an unspecific 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 IPF, HSCT and 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.