Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
37,875
result(s) for
"Pulmonary Fibrosis"
Sort by:
Who took my breath away ? : one man's fight against a fatal lung disease
\"In 2018, I was diagnosed with Idiopathic Pulmonary Fibrosis, a fatal lung disease that typically hits people in their 60s. Not the new I expected to hear a few weeks after turning 38. The universe sure has a strange way of making us feel special!\", back cover.
Book
Nintedanib in Progressive Fibrosing Interstitial Lung Diseases
In patients with a progressive interstitial lung disease, 62% of whom had a CT pattern of usual interstitial pneumonia, those who received nintedanib had a lower annual rate of decline in the forced vital capacity than those who received placebo at 52 weeks.
Journal Article
Novel Small-Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various
cellular models. GNS-3595 also prevented transforming growth factor β-induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.
Journal Article
Quantitative micro-CT-derived biomarkers elucidate age-related lung fibrosis in elder mice
Background
Idiopathic Pulmonary Fibrosis (IPF), prevalently affecting individuals over 60 years of age, has been mainly studied in young mouse models. The limited efficacy of current treatments underscores the need for animal models that better mimic an aged patient population. We addressed this by inducing pulmonary fibrosis in aged mice, using longitudinal micro-CT imaging as primary readout, with special attention to animal welfare.
Methods
A double bleomycin dose was administered to 18–24 months-old male C57Bl/6j mice to induce pulmonary fibrosis. Bleomycin dosage was reduced to as low as 75% compared to that commonly administered to young (8–12 weeks-old) mice, resulting in long-term lung fibrosis without mortality, complying with animal welfare guidelines. After fibrosis induction, animals received Nintedanib once-daily for two weeks and longitudinally monitored by micro-CT, which provided structural and functional biomarkers, followed by post-mortem histological analysis as terminal endpoint.
Results
Compared to young mice, aged animals displayed increased volume, reduced tissue density and function, and marked inflammation. This increased vulnerability imposed a bleomycin dosage reduction to the lowest tested level (2.5 µg/mouse), inducing a milder, yet persistent, fibrosis, while preserving animal welfare. Nintedanib treatment reduced fibrotic lesions and improved pulmonary function.
Conclusions
Our data identify a downsized bleomycin treatment that allows to achieve the best trade-off between fibrosis induction and animal welfare, a requirement for antifibrotic drug testing in aged lungs. Nintedanib displayed significant efficacy in this lower-severity disease model, suggesting potential patient stratification strategies. Lung pathology was quantitatively assessed by micro-CT, pointing to the value of longitudinal endpoints in clinical trials.
Journal Article
Molecular Mechanisms of Pulmonary Fibrogenesis and Its Progression to Lung Cancer: A Review
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. Despite the increasing research interest in the pathogenesis of IPF, unfavorable survival rates remain associated with this condition. Recently, novel therapeutic agents have been shown to control the progression of IPF. However, these drugs do not improve lung function and have not been tested prospectively in patients with IPF and coexisting lung cancer, which is a common comorbidity of IPF. Optimal management of patients with IPF and lung cancer requires understanding of pathogenic mechanisms and molecular pathways that are common to both diseases. This review article reflects the current state of knowledge regarding the pathogenesis of pulmonary fibrosis and summarizes the pathways that are common to IPF and lung cancer by focusing on the molecular mechanisms.
Journal Article
Spectrum of Fibrotic Lung Diseases
This review covers fibrotic pulmonary diseases. Although idiopathic pulmonary fibrosis is very common, the review focuses mainly on fibrotic diseases other than IPF. The biology, clinical presentation, and treatment of the more common disorders are discussed.
Journal Article
Pulmonary fibrosis: patterns and perpetrators
Pulmonary fibrosis occurs in a variety of clinical settings, constitutes a major cause of morbidity and mortality, and represents an enormous unmet medical need. However, the disease is heterogeneous, and the failure to accurately discern between forms of fibrosing lung diseases leads to inaccurate treatments. Pulmonary fibrosis occurring in the context of connective tissue diseases is often characterized by a distinct pattern of tissue pathology and may be amenable to immunosuppressive therapies. In contrast, idiopathic pulmonary fibrosis (IPF) is a progressive and lethal form of fibrosing lung disease that is recalcitrant to therapies that target the immune system. Although animal models of fibrosis imperfectly recapitulate IPF, they have yielded numerous targets for therapeutic intervention. Understanding the heterogeneity of these diseases and elucidating the final common pathways of fibrogenesis are critical for the development of efficacious therapies for severe fibrosing lung diseases.
Journal Article
Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline
This document provides clinical recommendations for the diagnosis of idiopathic pulmonary fibrosis (IPF). It represents a collaborative effort between the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society.
The evidence syntheses were discussed and recommendations formulated by a multidisciplinary committee of IPF experts. The evidence was appraised and recommendations were formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach.
The guideline panel updated the diagnostic criteria for IPF. Previously defined patterns of usual interstitial pneumonia (UIP) were refined to patterns of UIP, probable UIP, indeterminate, and alternate diagnosis. For patients with newly detected interstitial lung disease (ILD) who have a high-resolution computed tomography scan pattern of probable UIP, indeterminate, or an alternative diagnosis, conditional recommendations were made for performing BAL and surgical lung biopsy; because of lack of evidence, no recommendation was made for or against performing transbronchial lung biopsy or lung cryobiopsy. In contrast, for patients with newly detected ILD who have a high-resolution computed tomography scan pattern of UIP, strong recommendations were made against performing surgical lung biopsy, transbronchial lung biopsy, and lung cryobiopsy, and a conditional recommendation was made against performing BAL. Additional recommendations included a conditional recommendation for multidisciplinary discussion and a strong recommendation against measurement of serum biomarkers for the sole purpose of distinguishing IPF from other ILDs.
The guideline panel provided recommendations related to the diagnosis of IPF.
Journal Article
Predicting Outcomes in Idiopathic Pulmonary Fibrosis Using Automated Computed Tomographic Analysis
Quantitative computed tomographic (CT) measures of baseline disease severity might identify patients with idiopathic pulmonary fibrosis (IPF) with an increased mortality risk. We evaluated whether quantitative CT variables could act as a cohort enrichment tool in future IPF drug trials.
To determine whether computer-derived CT measures, specifically measures of pulmonary vessel-related structures (VRSs), can better predict functional decline and survival in IPF and reduce requisite sample sizes in drug trial populations.
Patients with IPF undergoing volumetric noncontrast CT imaging at the Royal Brompton Hospital, London, and St. Antonius Hospital, Utrecht, were examined to identify pulmonary function measures (including FVC) and visual and computer-derived (CALIPER [Computer-Aided Lung Informatics for Pathology Evaluation and Rating] software) CT features predictive of mortality and FVC decline. The discovery cohort comprised 247 consecutive patients, with validation of results conducted in a separate cohort of 284 patients, all fulfilling drug trial entry criteria.
In the discovery and validation cohorts, CALIPER-derived features, particularly VRS scores, were among the strongest predictors of survival and FVC decline. CALIPER results were accentuated in patients with less extensive disease, outperforming pulmonary function measures. When used as a cohort enrichment tool, a CALIPER VRS score greater than 4.4% of the lung was able to reduce the requisite sample size of an IPF drug trial by 26%.
Our study has validated a new quantitative CT measure in patients with IPF fulfilling drug trial entry criteria-the VRS score-that outperformed current gold standard measures of outcome. When used for cohort enrichment in an IPF drug trial setting, VRS threshold scores can reduce a required IPF drug trial population size by 25%, thereby limiting prohibitive trial costs. Importantly, VRS scores identify patients in whom antifibrotic medication prolongs life and reduces FVC decline.
Journal Article
Spatial transcriptomic and morpho-functional information derived from single mouse FFPE slides allows in-depth fingerprinting of lung fibrosis
Background
Transcriptome profiling by RNA sequencing (RNAseq) can provide insightful information on the molecular processes underlying disease development and progression. Although fresh tissue represents the preferred source material for RNAseq, here, we investigated the feasibility of applying RNAseq analysis to single 10 μm thick formalin-fixed and paraffin-embedded (FFPE) lung slides from the lungs of control and bleomycin (BLM)-treated mice. This approach aims at providing spatial-oriented transcriptomic data, that can be integrated with in vivo and ex vivo readouts obtained on the same sample, as a way to enhance the mechanistic information and biomarker/target discovery potential of preclinical models of fibrotic lung diseases.
Methods
RNAseq analysis was conducted on individual FFPE slides from the lungs of both controls and BLM-treated mice. The results were initially validated by comparison with publicly available bulk data from fresh-frozen (FF) mouse tissues, both untreated and BLM-treated, as well as human idiopathic pulmonary fibrosis (IPF) biopsies. Unsupervised cluster analysis was performed on Differentially Expressed Genes (DEGs) distinguishing untreated and BLM-treated fibrotic lung samples. For each sample, Pearson correlation analysis was used to compare expression levels of individual gene clusters with Ashcroft Scores and aeration compartments quantitatively assessed on the matched 2D micro-CT coronal slice.
Results
Over 90% of annotated genes within the FFPE dataset were shared with gene signatures retrieved from FF bulk datasets. Differentially modulated gene clusters were mainly found to be associated with extracellular matrix (ECM) organization, tissue remodeling, and inflammatory response pathways. For each sample, expression levels of individual gene clusters were highly correlated with 2D histology readouts and aeration compartments determined on matched 2D coronal slices by micro-CT imaging.
Conclusions
FFPE lung tissue represents a valuable alternative to fresh tissue for RNAseq analysis, allowing to achieve a more precise, spatially oriented picture of pulmonary disease development. This approach is thus instrumental to a better characterization of the molecular changes associated to each sample. It can also contribute to a more informed interpretation of histology and micro-CT imaging data, paving the way to the identification of translationally relevant biomarkers as well as novel candidate targets for the development of more effective therapeutic interventions.
Journal Article