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A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. KCa3.1 ion channels play a critical role in TGF?1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective KCa3.1 blocker senicapoc. 2?mm3 pieces of human lung parenchyma were cultured for 7?days in DMEM?±?TGF?1 (10?ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. Following 7 days of culture with TGF?1, 41 IPF- and fibrosis-associated genes were significantly upregulated. Immunohistochemical staining demonstrated increased expression of ECM proteins and fibroblast-specific protein after TGF?1-stimulation. Collagen secretion was significantly increased following TGF?1-stimulation. These pro-fibrotic responses were attenuated by senicapoc, but not by dexamethasone. This 7 day ex vivo model of human lung fibrogenesis recapitulates pro-fibrotic events evident in IPF and is sensitive to KCa3.1 channel inhibition. By maintaining the complex cell-cell and cell-matrix interactions of human tissue, and removing cross-species heterogeneity, this model may better predict drug efficacy in clinical trials and accelerate drug development in IPF. KCa3.1 channels are a promising target for the treatment of IPF.

SUBMITTER: Roach KM

PROVIDER: S-EPMC5762721 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis.

Roach Katy M KM Sutcliffe Amanda A Matthews Laura L Elliott Gill G Newby Chris C Amrani Yassine Y Bradding Peter P

Scientific reports 20180110 1

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. KCa3.1 ion channels play a critical role in TGFβ1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective KCa3.1 blocker senicapoc. 2 mm3 pieces of human lung parenchyma were cultured for 7 days in DMEM ± TGFβ1 (10 ng/ml) and pro-fibrotic pa ...[more]

PMID: 29321510

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Project description:ObjectiveSecretoglobin (SCGB) 3A2 is a novel lung-enriched cytokine, previously shown to exhibit anti-inflammatory, growth factor, and anti-fibrotic activities. The latter activity was demonstrated using exogenously-administered recombinant SCGB3A2 in the bleomycin (BLM)-induced pulmonary fibrosis model. Whether SCGB3A2 exhibits anti-fibrotic activity in vivo is not known.MethodsMice null for the Scgb3a2 gene were subjected to the BLM-induced pulmonary fibrosis model, and the severity of pulmonary fibrosis determined using histological and biochemical methods.ResultsBLM treatment caused weight loss of both Scgb3a2-null and wild-type mice, however, the loss was far more pronounced in BLM-treated Scgb3a2-null than wild-type mice, and the weight of day 21 of BLM-treated Scgb3a2-null mice was about half of that of BLM-treated wild-type mice. Hematoxylin & Eosin, Masson Trichrome, and Sirius Red staining of lung sections, Ashcroft fibrosis scores, hydroxyproline contents, and the levels of mRNAs encoding various collagens demonstrated that BLM-treated Scgb3a2-null mouse lungs had more severe fibrosis than those of wild-type mouse lungs. Total and differential inflammatory cell numbers in bronchoalveolar lavage fluids, and levels of lung mRNAs including those encoding Th2 cytokines such as IL-4 and profibrotic cytokines such as TGFβ were higher in BLM-treated Scgb3a2-null mouse lungs as compared to those of wild-type mouse lungs. In contrast, mRNAs encoding surfactant proteins A, B, C, and D, and SCGB1A1 did not differ between BLM-treated Scgb3a2-null and wild-type mouse lungs.ConclusionThe role of SCGB3A2 in fibrosis was revisited using Scgb3a2-null mice and littermate controls in the BLM-induced pulmonary fibrosis model. The pulmonary fibrosis in the Scgb3a2-null mice was more severe than the wild-type controls, thus establishing that SCGB3A2 has anti-fibrotic activity in vivo. Importantly, surfactant proteins and SCGB1A1 appear not to be involved in the susceptibility of Scgb3a2-null mice to BLM-induced pulmonary fibrosis.

Project description:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. METHODS:We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ?10% decline in FVC or???15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6?months were classified as progression group, while the other patients were classified as stable group. RESULTS:Forty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6?months significantly decreased compared with the progression group (SP-A: 3?months -?6.0% vs 16.7%, 6?months -?10.2% vs 20.2%, KL-6: 3?months -?9.2% vs 6.7%, 6?months -?15.0% vs 12.1%, p?<?0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r?=?-?0.46 and r?=?-?0.39, p?<?0.01, respectively) and %DLco (r?=?-?0.67 and r?=?-?0.54, p?<?0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3?months and 6?months was found to predict the outcomes at 6?months (odds ratios: 0.89 and 0.88, respectively). CONCLUSIONS:Changes in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.

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

A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis.

Publications

A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis.

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