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.

Pirfenidone in restrictive allograft syndrome after lung transplantation: A case series

“…2,3,[9][10][11] Therefore, antifibrotic therapies may contribute to maintenance of allograft function and improved outcomes in RAS. As such, the pathophysiologic mechanisms leading to tissue fibrosis in the lung allograft in RAS are thought to be, at last partially, similar to those in IPF.…”

“…17 Notably, 3 patients were bridged to redotransplantation with pirfenidone for 11 (5)(6)(7)(8)(9)(10)(11)(12) Given that OB lesions are present in the majority of RAS patients, and additionally, the interstitial compartments are expanded and alveolar airspaces are obliterated by accumulation of fibrous connective tissue, 13 treatment with pirfenidone may perhaps even prove to be more effective in RAS, although it may take several weeks before its beneficial effects might become evident, as is seen in IPF. Our findings provide further evidence that pirfenidone appears to be safe and may attenuate the rate of decline in lung function (FVC and FEV 1 ) in patients with RAS, confirming our findings in a prior case.…”

“…[1][2][3][4] RAS is characterized by restrictive pulmonary physiology and persistent pleuroparenchymal abnormalities, such as peripheral ground-glass opacities, consolidation, traction bronchiectasis, architectural distortion, and (sub)pleural thickening on chest computed tomography (CT) scan. [1][2][3][5][6][7][8] On histology, obliterative bronchiolitis (OB), together with pleuroparenchymal fibroelastosis, nonspecific interstitial pneumonia, or other interstitial and fibrotic changes can be seen, [9][10][11] which is associated with marked local T and B cell accumulation. 12,13 Importantly, RAS carries an unfavorable prognosis with a median survival of 1-1.5 years after disease onset.…”

“…Notably, 3 patients were bridged to redo-transplantation with pirfenidone for 11 (5)(6)(7)(8)(9)(10)(11)(12) months and are currently alive, while 3 other patients demonstrate long-term stabilization of pulmonary function after 26.6 (range 18.4-46.6) months of treatment. We retrospectively assessed all lung transplant recipients with RAS who were treated with pirfenidone for at least 3 months (n = 11) in our lung transplant center and report on their long-term outcomes following initiation of pirfenidone.…”

“…Pirfenidone appears to attenuate the decline in forced vital capacity and forced expiratory volume in 1 second. Notably, 3 patients were bridged to redo-transplantation with pirfenidone for 11 (5)(6)(7)(8)(9)(10)(11)(12) months and are currently alive, while 3 other patients demonstrate long-term stabilization of pulmonary function after 26.6 (range 18.4-46.6) months of treatment. Median overall 3-year survival after RAS diagnosis was 54.5%.…”