Metalloproteinase Profiling in Lung Transplant Recipients With Good Outcome and Bronchiolitis Obliterans Syndrome

Heijink, Irene H.; Rozeveld, Dennie; Heide, S. van der; Bij, Wim van der; Bischoff, Rainer; Oosterhout, Antoon J. van; Toorn, Marco van der

doi:10.1097/tp.0000000000000602

Cited by 13 publications

(17 citation statements)

References 38 publications

(47 reference statements)

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“…MMPs are known to degrade ECM components and excess in MMP may be responsible for epithelial damage, fibrosis, and uncontrolled tissue remodeling. MMP‐9 has been detected in BAL early after transplantation and is overexpressed in patients with BOS . Moreover, it is involved in airway remodeling as MMP‐9 deficiency reduces airway obliteration in a mouse model of tracheal allograft .…”

Section: Discussionmentioning

confidence: 99%

T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

Pain

Royer

Loy

et al. 2017

American Journal of Transplantation

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Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. CLAD manifests as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Alloimmune reactions and epithelial-to-mesenchymal transition have been suggested in BOS. However, little is known regarding the role of allogenicity in epithelial cell differentiation. Primary human bronchial epithelial cells (BECs) were treated with activated T cells in the presence or absence of transforming growth factor (TGF)-β. The expression of epithelial and mesenchymal markers was investigated. The secretion of inflammatory cytokines and matrix metalloproteinase (MMP)-9 was measured in culture supernatants and in plasma from lung transplant recipients (LTRs): 49 stable, 29 with BOS, and 16 with RAS. We demonstrated that C-C motif chemokine 2 secreted by T cells supports TGF-β-induced MMP-9 production by BECs after binding to C-C chemokine receptor type 2. Longitudinal investigation in LTRs revealed a rise in plasma MMP-9 before CLAD onset. Multivariate analysis showed that plasma MMP-9 was independently associated with BOS (odds ratio [OR] = 6.19, p = 0.002) or RAS (OR = 3.9, p = 0.024) and predicted the occurrence of CLAD 12 months before the functional diagnosis. Thus, immune cells support airway remodeling through the production of MMP-9. Plasma MMP-9 is a potential predictive biomarker of CLAD.

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Section: Discussionmentioning

confidence: 99%

T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

Pain

Royer

Loy

et al. 2017

American Journal of Transplantation

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“…Because of the lack of sensitivity of conventional morphology in TBBs for CLAD, we and others started looking for means to supplement conventional histological analysis of invasively sampled specimens, which would allow an earlier and more specific diagnosis of CLAD, making earlier treatment with potentially better outcome possible. 7,19 In the present study, we wanted to validate the predictive value of a set of molecular markers for CLAD, as previously established by us in lung explants, in a retrospective analysis of TBBs from LTx patients. 7,22 Figure 4 Relative mRNA expression levels for IL-6, matrix metalloproteinase 1 (MMP1), Sma and Mad-related protein 1 (SMAD1), thrombospondin 1 (THBS1), and bone morphogenetic protein 4 (BMP4) in lung biopsy specimens of rapid-onset chronic lung allograft dysfunction (CLAD) and the stable groups.…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiling in Lung Biopsies of Human Pulmonary Allografts to Predict Chronic Lung Allograft Dysfunction

Jonigk

Izykowski

Rische

et al. 2015

The American Journal of Pathology

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Chronic lung allograft dysfunction (CLAD) is the main reason for poor long-term outcome of lung transplantation, with bronchiolitis obliterans (BO) representing the predominant pathological feature. BO is defined as a progressive fibrous obliteration of the small airways, thought to be triggered by a combination of nonimmune bronchial injury and alloimmune and autoimmune mechanisms. Because biopsy samples are too insensitive to reliably detect BO and a decline in lung function test results, which is clinically used to define CLAD, does not detect early stages, there is need for alternative biomarkers for early diagnosis. Herein, we analyzed the cellular composition and differential expression of 45 tissue remodeling-associated genes in transbronchial lung biopsy specimens from two cohorts with 18 patients each: patients who did not develop CLAD within 3 years after transplantation (48 biopsy specimens) and patients rapidly developing CLAD within the first 3 postoperative years (57 biopsy specimens). Integrating the mRNA expression levels of the five most significantly dysregulated genes from the transforming growth factor-β axis (BMP4, IL6, MMP1, SMAD1, and THBS1) into a score, patient groups could be confidently separated and the outcome predicted (P < 0.001). We conclude that overexpression of fibrosis-associated genes may be valuable as a tissue-based molecular biomarker to more accurately diagnose or predict the development of CLAD.

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“…MMP1 is implicated in cell division, migration, differentiation and apoptosis via intracellular activity. In our own tissue-based molecular expression analyses, we recently demonstrated, in contrast to BAL analyses, an upregulation of MMP1 in TBBs of BOS patients [7,44,45]. Here, via compartmentspecific molecular expression analysis MMP1 was even more specifically localised to AFE areas.…”

Section: Discussionmentioning

confidence: 69%

Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation

Jonigk

Rath

Borchert

et al. 2016

The Journal of Pathology CR

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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.

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Metalloproteinase Profiling in Lung Transplant Recipients With Good Outcome and Bronchiolitis Obliterans Syndrome

Cited by 13 publications

References 38 publications

T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

T Cells Promote Bronchial Epithelial Cell Secretion of Matrix Metalloproteinase-9 via a C-C Chemokine Receptor Type 2 Pathway: Implications for Chronic Lung Allograft Dysfunction

Molecular Profiling in Lung Biopsies of Human Pulmonary Allografts to Predict Chronic Lung Allograft Dysfunction

Comparative analysis of morphological and molecular motifs in bronchiolitis obliterans and alveolar fibroelastosis after lung and stem cell transplantation

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