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Registration of the extracellular matrix components constituting the fibroblastic focus in idiopathic pulmonary fibrosis.

ABSTRACT: The extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) drives fibrosis progression; however, the ECM composition of the fibroblastic focus (the hallmark lesion in IPF) and adjacent regions remains incompletely defined. Herein, we serially sectioned IPF lung specimens constructed into tissue microarrays and immunostained for ECM components reported to be deregulated in IPF. Immunostained sections were imaged, anatomically aligned, and 3D reconstructed. The myofibroblast core of the fibroblastic focus (defined by collagen I, ?-smooth muscle actin, and procollagen I immunoreactivity) was associated with collagens III, IV, V, and VI; fibronectin; hyaluronan; and versican immunoreactivity. Hyaluronan immunoreactivity was also present at the fibroblastic focus perimeter and at sites where early lesions appear to be forming. Fibrinogen immunoreactivity was often observed at regions of damaged epithelium lining the airspace and the perimeter of the myofibroblast core but was absent from the myofibroblast core itself. The ECM components of the fibroblastic focus were distributed in a characteristic and reproducible manner in multiple patients. This information can inform the development of high-fidelity model systems to dissect mechanisms by which the IPF ECM drives fibrosis progression.

SUBMITTER: Herrera J

PROVIDER: S-EPMC6485370 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Registration of the extracellular matrix components constituting the fibroblastic focus in idiopathic pulmonary fibrosis.

Herrera Jeremy J Forster Colleen C Pengo Thomas T Montero Angeles A Swift Joe J Schwartz Martin A MA Henke Craig A CA Bitterman Peter B PB

JCI insight 20190110 1

The extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) drives fibrosis progression; however, the ECM composition of the fibroblastic focus (the hallmark lesion in IPF) and adjacent regions remains incompletely defined. Herein, we serially sectioned IPF lung specimens constructed into tissue microarrays and immunostained for ECM components reported to be deregulated in IPF. Immunostained sections were imaged, anatomically aligned, and 3D reconstructed. The myofibroblast core of the ...[more]

PMID: 30626754

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Project description:Fibroblastic foci (FF) are characteristic features of usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) and one cardinal feature thought to represent a key mechanism of pathogenesis. Hence, FF have a high impact on UIP/IPF diagnosis in current guidelines. However, although less frequent, these histomorphological hallmarks also occur in other fibrotic pulmonary diseases. Currently, there is therefore a gap in knowledge regarding the underlying molecular similarities and differences of FF in different disease entities. In this work, we analyzed the compartment-specific gene expression profiles of FF in IPF and sarcoidosis in order to elucidate similarities and differences as well as shared pathomechanisms. For this purpose, we used laser capture microdissection, mRNA and protein expression analysis. Biological pathway analysis was performed using two different gene expression databases. As control samples, we used healthy lung tissue that was donated but not used for lung transplantation. Based on Holm Bonferroni corrected expression data, mRNA expression analysis revealed a significantly altered expression signature for 136 out of 760 genes compared to healthy controls while half of these showed a similar regulation in both groups. Immunostaining of selected markers from each group corroborated these results. However, when comparing all differentially expressed genes with the fdr-based expression data, only 2 of these genes were differentially expressed between sarcoidosis and IPF compared to controls, i.e., calcium transport protein 1 (CAT1) and SMAD specific E3 ubiquitin protein ligase 1 (SMURF1), both in the sarcoidosis group. Direct comparison of sarcoidosis and IPF did not show any differentially regulated genes independent from the statistical methodology. Biological pathway analysis revealed a number of fibrosis-related pathways pronounced in IPF without differences in the regulatory direction. These results demonstrate that FF of end-stage IPF and sarcoidosis lungs, although different in initiation, are similar in gene and protein expression, encouraging further studies on the use of antifibrotic agents in sarcoidosis.

Project description:ObjectivesEvaluation and follow-up of idiopathic pulmonary fibrosis (IPF) mainly rely on high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs). The elastic registration technique can quantitatively assess lung shrinkage. We aimed to investigate the correlation between lung shrinkage and morphological and functional deterioration in IPF.MethodsPatients with IPF who underwent at least two HRCT scans and PFTs were retrospectively included. Elastic registration was performed on the baseline and follow-up HRCTs to obtain deformation maps of the whole lung. Jacobian determinants were calculated from the deformation fields and after logarithm transformation, log_jac values were represented on color maps to describe morphological deterioration, and to assess the correlation between log_jac values and PFTs.ResultsA total of 69 patients with IPF (male 66) were included. Jacobian maps demonstrated constriction of the lung parenchyma marked at the lung base in patients who were deteriorated on visual and PFT assessment. The log_jac values were significantly reduced in the deteriorated patients compared to the stable patients. Mean log_jac values showed positive correlation with baseline percentage of predicted vital capacity (VC%) (r = 0.394, p < 0.05) and percentage of predicted forced vital capacity (FVC%) (r = 0.395, p < 0.05). Additionally, the mean log_jac values were positively correlated with pulmonary vascular volume (r = 0.438, p < 0.01) and the number of pulmonary vascular branches (r = 0.326, p < 0.01).ConclusionsElastic registration between baseline and follow-up HRCT was helpful to quantitatively assess the morphological deterioration of lung shrinkage in IPF, and the quantitative indicator log_jac values were significantly correlated with PFTs.Key points• The elastic registration on HRCT was helpful to quantitatively assess the deterioration of IPF. • Jacobian logarithm was significantly reduced in deteriorated patients and mean log_jac values were correlated with PFTs. • The mean log_jac values were related to the changes of pulmonary vascular volume and the number of vascular branches.

Dataset Information

Registration of the extracellular matrix components constituting the fibroblastic focus in idiopathic pulmonary fibrosis.

Publications

Registration of the extracellular matrix components constituting the fibroblastic focus in idiopathic pulmonary fibrosis.

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