Toll-Interacting Protein and Altered Lung Microbiota in Idiopathic Pulmonary Fibrosis.
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ABSTRACT:
SUBMITTER: Lipinski JH
PROVIDER: S-EPMC9887421 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Toll-Interacting Protein and Altered Lung Microbiota in Idiopathic Pulmonary Fibrosis.
Lipinski Jay H JH Erb-Downward John R JR Huffnagle Gary B GB Flaherty Kevin R KR Martinez Fernando J FJ Moore Bethany B BB Dickson Robert P RP Noth Imre I O'Dwyer David N DN
American journal of respiratory and critical care medicine 20220701 2
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Project description: Not available
| S-EPMC6909839 | biostudies-literature
Project description:RationaleGap junctions are membrane channels formed by an array of connexins which links adjacent cells realizing an electro- metabolic synapse. Connexin-mediated communication is crucial in the regulation of cell growth, differentiation, and development. The activation and proliferation of phenotypically altered fibroblasts are central events in the pathogenesis of idiopathic pulmonary fibrosis. We sought to evaluate the role of connexin-43, the most abundant gap-junction subunit in the human lung, in the pathogenesis of this condition.MethodsWe investigated the transcription and protein expression of connexin-43 and the gap-junctional intercellular communication (GJIC) in 5 primary lung fibroblast lines derived from normal subjects (NF) and from 3 histologically proven IPF patients (FF).ResultsHere we show that connexin-43 mRNA was significantly reduced in FF as demonstrated by standard and quantitative RT-PCR. GJIC was functionally evaluated by means of flow-cytometry. In order to demonstrate that dye spreading was taking place through gap junctions, we used carbenoxolone as a pharmacological gap-junction blocker. Carbenoxolone specifically blocked GJIC in our system in a concentration dependent manner. FF showed a significantly reduced homologous GJIC compared to NF. Similarly, GJIC was significantly impaired in FF when a heterologous NF line was used as dye donor, suggesting a complete defect in GJIC of FF.ConclusionThese results suggest a novel alteration in primary lung fibroblasts from IPF patients. The reduced Cx43 expression and the associated alteration in cell-to-cell communication may justify some of the known pathological characteristic of this devastating disease that still represents a challenge to the medical practice.
| S-EPMC1594576 | biostudies-literature
Project description:RationaleDNA methylation is an important epigenetic mechanism, which often occurs in response to environmental stimuli and is crucial in regulating gene expression. It is likely that epigenetic alterations contribute to pathogenesis in idiopathic pulmonary fibrosis (IPF).ObjectivesTo determine the DNA methylation changes in IPF and their effects on gene expression.MethodsTotal DNA methylation and DNA methyltransferase expression were compared in IPF and normal control lung tissues. IPF and normal tissues were subjected to comparative analysis of genome-wide DNA methylation and RNA expression using DNA hybridization to the Illumina HumanMethylation27 BeadChip and RNA hybridization to Illumina HumanHT-12 BeadChip. Functional analyses of differentially expressed and differentially methylated genes were done. Selected genes were validated at DNA, RNA, and protein levels.Measurements and main resultsDNA methylation status was altered in IPF. IPF samples demonstrated higher DNA methyltransferase expression without observed alterations in global DNA methylation. Genome-wide differences in DNA methylation status and RNA expression were demonstrated by array hybridization. Among the genes whose DNA methylation status and RNA expression were both significantly altered, 16 genes were hypermethylated in DNA associated with decreased mRNA expression or vice versa. We validated CLDN5, ZNF467, TP53INP1, and DDAH1 genes at the level of DNA methylation status, RNA, and protein-level expression.ConclusionsChanges in DNA methylation correspond to altered mRNA expression of a number of genes, some with known and others with previously uncharacterized roles in IPF, suggesting that DNA methylation is important in the pathogenesis of IPF.
| S-EPMC3480526 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2012-06-30 | GSE35147 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown origin with a highly variable and unpredictable clinical course. Polymorphisms and environmentally induced epigenetic variations seem to determine individual susceptibility to the development of lung fibrosis.We have studied circulating epitopes on cell-free nucleosomes (cfnucleosomes) in 50 IPF patients. We have compared untreated IPF (n = 23) with IPF receiving antifibrotic therapy (n = 27) and healthy subjects (HS) (n = 27). We analyzed serum levels of five cfnucleosomes including bound HMGB1 (nucleosomes adducted to high-mobility growth protein B1), mH2A1.1 (nucleosomes containing the histone variant mH2A1.1), 5mC (nucleosomes associated with methylated DNA), and H3K9Ac and H3K27Ac (nucleosomes associated with histone H3 acetylated at lysine 9 or 27 residue).Our findings showed that serum levels of bound HMGB1, mH2A1.1, 5mC, H3K9Ac, and H3K27Ac were significantly lower in IPF patients than in HS (p < 0.001, p < 0.001, p < 0.01, p < 0.001, and p < 0.0001, respectively). Moreover, we found differences in epigenetic profiles between untreated IPF patients and those receiving anti-fibrotic therapy with mH2A1.1 and 5mC being significantly lower in untreated than in treated patients (p < 0.01 and p < 0.05, respectively). Combination of four cfnucleosomes (HMGB1, 5mC, H3K9Ac, and H3K27Ac) allow to discriminate IPF vs HS with a good coefficient of determination (R2 = 0.681). The AUC for the ROC curve computed by this logistic regression was 0.93 (p < 0.001) with 91% sensitivity at 80% specificity.Our observations showed that cfnucleosomes (bound HMGB1, mH2A1.1, 5mC, H3K9Ac, and H3K27Ac) might have potential as biomarkers for diagnosis and treatment response. These results deserve further validation in longitudinal cohorts.
| S-EPMC5558769 | biostudies-other
Project description:Autophagy, apoptosis, and the unfolded protein response (UPR) are fundamental biological processes essential for manifold cellular functions in health and disease. Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal pulmonary disorder associated with aging that has limited therapies, reflecting our incomplete understanding. We conducted an observational study linking molecular markers of cell stress response pathways (UPR: BiP, XBP1; apoptosis: cleaved caspase-3; autophagy: LC3β) in lung tissues from IPF patients and correlated the expression of these protein markers to each subject's lung function measures. We hypothesized that changes in lung tissue expression of apoptosis, autophagy, and UPR markers correlate with lung function deficits in IPF. The cell stress markers BiP, XBP1, LC3β puncta, and cleaved caspase-3 were found to be elevated in IPF lungs compared to non-IPF lungs, and, further, BiP and cleaved caspase-3 co-localized in IPF lungs. Considering lung function independently, we observed that increased XBP1, BiP, and cleaved caspase-3 were each associated with reduced lung function (FEV1, FVC, TLC, RV). However, increased lung tissue expression of LC3β puncta was significantly associated with increased diffusion capacity (DLCO), an indicator of alveolar-capillary membrane function. Similarly, the co-localization of UPR (XBP1, BiP) and autophagy (LC3β puncta) markers was positively correlated with increased lung function (FEV1, FVC, TLC, DLCO). However, the presence of LC3β puncta can indicate either autophagy flux inhibition or activation. While the nature of our observational cross-sectional study design does not allow conclusions regarding causal links between increased expression of these cell stress markers, lung fibrosis, and lung function decline, it does provide some insights that are hypothesis-generating and suggests that within the milieu of active UPR, changes in autophagy flux may play an important role in determining lung function. Further research is necessary to investigate the mechanisms linking UPR and autophagy in IPF and how an imbalance in these cell stress pathways can lead to progressive fibrosis and loss of lung function. We conclude by presenting five testable hypotheses that build on the research presented here. Such an understanding could eventually lead to the development of much-needed therapies for IPF.
| S-EPMC8307368 | biostudies-literature
Project description:Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host-microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes.
| S-EPMC8779068 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease characterised by decline in lung function. We evaluated trajectories of forced vital capacity (FVC) and diffusing capacity (DLco) in a cohort of patients with IPF.MethodsPatients with IPF that was diagnosed or confirmed at the enrolling centre in the previous 6 months were enrolled into the IPF-PRO Registry between June 2014 and October 2018. Patients were followed prospectively, with lung function data collected as part of routine clinical care. Mean trajectories of FVC and DLco % predicted in all patients and in subgroups by characteristics assessed at enrolment were estimated using a joint model that accounted for factors such as disease severity and visit patterns.ResultsOf 1002 patients in the registry, 941 had ≥ 1 FVC and/or DLco measurement after enrolment. The median (Q1, Q3) follow-up period was 35.1 (18.9, 47.2) months. Overall, mean estimated declines in FVC and DLco % predicted were 2.8% and 2.9% per year, respectively. There was no evidence that the mean trajectories of FVC or DLco had a non-linear relationship with time at the population level. Patients who were male, white, had a family history of ILD, were using oxygen, or had prior/current use of antifibrotic therapy at enrolment had greater rates of decline in FVC % predicted. Patients who were male or white had greater rates of decline in DLco % predicted.ConclusionsData from the IPF-PRO Registry suggest a constant rate of decline in lung function over a prolonged period, supporting the inexorably progressive nature of IPF. A graphical abstract summarising the data in this manuscript is available at: https://www.usscicomms.com/respiratory/IPF-PRORegistry_LungFunctionTrajectories .Trial registrationNCT01915511.
| S-EPMC10463468 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by abnormal fibroblast accumulation in the lung leading to extracellular matrix deposition and remodeling that compromise lung function. However, the mechanisms of interstitial invasion and remodeling by lung fibroblasts remain poorly understood. The invadosomes, initially described in cancer cells, consist of actin-based adhesive structures that coordinate with numerous other proteins to form a membrane protrusion capable of degrading the extracellular matrix to promote their invasive phenotype. In this regard, we hypothesized that invadosome formation may be increased in lung fibroblasts from patients with IPF. Public RNAseq datasets from control and IPF lung tissues were used to identify differentially expressed genes associated with invadosomes. Lung fibroblasts isolated from bleomycin-exposed mice and IPF patients were seeded with and without the two approved drugs for treating IPF, nintedanib or pirfenidone on fluorescent gelatin-coated coverslips for invadosome assays. Several matrix and invadosome-associated genes were increased in IPF tissues and in IPF fibroblastic foci. Invadosome formation was significantly increased in lung fibroblasts isolated from bleomycin-exposed mice and IPF patients. The degree of lung fibrosis found in IPF tissues correlated strongly with invadosome production by neighboring cells. Nintedanib suppressed IPF and PDGF-activated lung fibroblast invadosome formation, an event associated with inhibition of the PDGFR/PI3K/Akt pathway and TKS5 expression. Fibroblasts derived from IPF lung tissues express a pro-invadosomal phenotype, which correlates with the severity of fibrosis and is responsive to antifibrotic treatment.
| S-EPMC9820272 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM). Caveolin-1 (cav-1), a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin (BLM)-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 (TGF-beta1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.
| S-EPMC1850940 | biostudies-literature