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The European Respiratory Journal Mar 2023This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate... (Review)
Review
This expert group consensus statement emphasises the need for standardising the definition of progressive fibrosing interstitial lung diseases (F-ILDs), with an accurate initial diagnosis being of paramount importance in ensuring appropriate initial management. Equally, case-by-case decisions on monitoring and management are essential, given the varying presentations of F-ILDs and the varying rates of progression. The value of diagnostic tests in risk stratification at presentation and, separately, the importance of a logical monitoring strategy, tailored to manage the risk of progression, are also stressed. The term "progressive pulmonary fibrosis" (PPF) exactly describes the entity that clinicians often face in practice. The importance of using antifibrotic therapy early in PPF (once initial management has failed to prevent progression) is increasingly supported by evidence. Artificial intelligence software for high-resolution computed tomography analysis, although an exciting tool for the future, awaits validation. Guidance is provided on pulmonary rehabilitation, oxygen and the use of non-invasive ventilation focused specifically on the needs of ILD patients with progressive disease. PPF should be differentiated from acute deterioration due to drug-induced lung toxicity or other forms of acute exacerbations. Referral criteria for a lung transplant are discussed and applied to patient needs in severe diseases where transplantation is not realistic, either due to access limitations or transplantation contraindications. In conclusion, expert group consensus guidance is provided on the diagnosis, treatment and monitoring of F-ILDs with specific focus on the recognition of PPF and the management of pulmonary fibrosis progressing despite initial management.
Topics: Humans; Pulmonary Fibrosis; Artificial Intelligence; Disease Progression; Lung Diseases, Interstitial; Fibrosis; Idiopathic Pulmonary Fibrosis
PubMed: 36517177
DOI: 10.1183/13993003.03187-2021 -
Molecular Aspects of Medicine Feb 2019Idiopathic pulmonary fibrosis (IPF) is a progressive and terminal lung disease with no known cure. IPF is a disease of aging, with median age of diagnosis over 65 years.... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive and terminal lung disease with no known cure. IPF is a disease of aging, with median age of diagnosis over 65 years. Median survival is between 3 and 5 years after diagnosis. IPF is characterized primarily by excessive deposition of extracellular matrix (ECM) proteins by activated lung fibroblasts and myofibroblasts, resulting in reduced gas exchange and impaired pulmonary function. Growing evidence supports the concept of a pro-fibrotic environment orchestrated by underlying factors such as genetic predisposition, chronic injury and aging, oxidative stress, and impaired regenerative responses may account for disease development and persistence. Currently, two FDA approved drugs have limited efficacy in the treatment of IPF. Many of the genes and gene networks associated with lung development are induced or activated in IPF. In this review, we analyze current knowledge in the field, gained from both basic and clinical research, to provide new insights into the disease process, and potential approaches to treatment of pulmonary fibrosis.
Topics: Animals; Biomarkers; Cellular Microenvironment; Disease Susceptibility; Homeodomain Proteins; Humans; Myofibroblasts; Pulmonary Fibrosis; Signal Transduction; Stromal Cells; Trans-Activators; Transforming Growth Factor beta
PubMed: 30130563
DOI: 10.1016/j.mam.2018.08.004 -
International Journal of Molecular... Nov 2022Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary... (Review)
Review
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.
Topics: Humans; Pulmonary Fibrosis; Prognosis; Lung; Pneumonia; Fibrosis; Inflammation
PubMed: 36499287
DOI: 10.3390/ijms232314959 -
Autoimmunity Reviews Jul 2017Anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides are immune-mediated disorders that primarily affect small blood vessels of the airway and kidneys. Lung... (Review)
Review
Anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides are immune-mediated disorders that primarily affect small blood vessels of the airway and kidneys. Lung involvement, one of the hallmarks of microscopic polyangiitis and granulomatosis with polyangiitis, is associated with increased mortality and morbidity. In recent years, several retrospective series and case reports have described the association of interstitial lung disease (ILD) and ANCA vasculitis, particularly those positive for ANCA specific for myeloperoxidase. In the majority of these patients pulmonary fibrosis occurs concurrently or predates the diagnosis of ANCA vasculitis. More importantly, these studies have shown that ILD has an adverse impact on the long-term prognosis of ANCA vasculitis. This review focuses on the main clinical and radiologic features of pulmonary fibrosis associated with anti-neutrophil cytoplasmic antibodies. Major histopathology features, prognosis and therapeutic options are summarized.
Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung; Lung Diseases, Interstitial; Pulmonary Fibrosis; Tomography, X-Ray Computed; Vasculitis
PubMed: 28479484
DOI: 10.1016/j.autrev.2017.05.008 -
Redox Biology Jun 2020Mechanisms underlying the pathogenesis of pulmonary fibrosis remain incompletely understood. Emerging evidence suggests changes in mitochondrial quality control are a... (Review)
Review
Mechanisms underlying the pathogenesis of pulmonary fibrosis remain incompletely understood. Emerging evidence suggests changes in mitochondrial quality control are a critical determinant in many lung diseases, including chronic obstructive pulmonary disease, asthma, pulmonary hypertension, acute lung injury, lung cancer, and in the susceptibility to pulmonary fibrosis. Once thought of as the kidney-bean shaped powerhouses of the cell, mitochondria are now known to form interconnected networks that rapidly and continuously change their size to meet cellular metabolic demands. Mitochondrial quality control modulates cell fate and homeostasis, and diminished mitochondrial quality control results in mitochondrial dysfunction, increased reactive oxygen species (ROS) production, reduced ATP production, and often induces intrinsic apoptosis. Here, we review the role of the mitochondria in alveolar epithelial cells, lung macrophages, and fibroblasts within the context of pulmonary fibrosis.
Topics: Alveolar Epithelial Cells; Apoptosis; Humans; Mitochondria; Pulmonary Fibrosis; Reactive Oxygen Species
PubMed: 31928788
DOI: 10.1016/j.redox.2020.101426 -
Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets.Matrix Biology : Journal of the... Oct 2018Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disease of the lung that is marked by progressive decline in pulmonary function and ultimately respiratory... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disease of the lung that is marked by progressive decline in pulmonary function and ultimately respiratory failure. Genetic and environmental risk factors have been identified that indicate injury to, and dysfunction of the lung epithelium is central to initiating the pathogenic process. Following injury to the lung epithelium, growth factors, matrikines and extracellular matrix driven signaling together activate a variety of repair pathways that lead to inflammatory cell recruitment, fibroblast proliferation and expansion of the extracellular matrix, culminating in tissue fibrosis. This tissue fibrosis then leads to changes in the biochemical and biomechanical properties of the extracellular matrix, which potentiate profibrotic mechanisms through a "feed-forward cycle." This review provides an overview of the interactions of the pathogenic mechanisms of IPF with a focus on epithelial-mesenchymal crosstalk and the extracellular matrix as a therapeutic target for idiopathic pulmonary fibrosis.
Topics: Epithelial-Mesenchymal Transition; Extracellular Matrix; Humans; Idiopathic Pulmonary Fibrosis; Lung; Molecular Targeted Therapy; Signal Transduction
PubMed: 29625182
DOI: 10.1016/j.matbio.2018.03.021 -
Nature Communications Nov 2022Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays...
Pulmonary fibrosis is a chronic interstitial lung disease that causes irreversible and progressive lung scarring and respiratory failure. Activation of fibroblasts plays a central role in the progression of pulmonary fibrosis. Here we show that platelet endothelial aggregation receptor 1 (PEAR1) in fibroblasts may serve as a target for pulmonary fibrosis therapy. Pear1 deficiency in aged mice spontaneously causes alveolar collagens accumulation. Mesenchyme-specific Pear1 deficiency aggravates bleomycin-induced pulmonary fibrosis, confirming that PEAR1 potentially modulates pulmonary fibrosis progression via regulation of mesenchymal cell function. Moreover, single cell and bulk tissue RNA-seq analysis of pulmonary fibroblast reveals the expansion of Activated-fibroblast cluster and enrichment of marker genes in extracellular matrix development in Pear1 fibrotic lungs. We further show that PEAR1 associates with Protein Phosphatase 1 to suppress fibrotic factors-induced intracellular signalling and fibroblast activation. Intratracheal aerosolization of monoclonal antibodies activating PEAR1 greatly ameliorates pulmonary fibrosis in both WT and Pear1-humanized mice, significantly improving their survival rate.
Topics: Mice; Animals; Pulmonary Fibrosis; Mice, Inbred C57BL; Fibroblasts; Extracellular Matrix; Bleomycin
PubMed: 36402779
DOI: 10.1038/s41467-022-34870-w -
BMC Pulmonary Medicine Dec 2021Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic... (Comparative Study)
Comparative Study Meta-Analysis
Efficacy of antifibrotic drugs, nintedanib and pirfenidone, in treatment of progressive pulmonary fibrosis in both idiopathic pulmonary fibrosis (IPF) and non-IPF: a systematic review and meta-analysis.
BACKGROUND
Research questions To compare the efficacy of nintedanib and pirfenidone in the treatment of progressive pulmonary fibrosis; and to compare the efficacy of anti-fibrotic therapy (grouping nintedanib and pirfenidone together) in patients with IPF versus patients with progressive lung fibrosis not classified as IPF.
STUDY DESIGN AND METHODS
A search of databases including MEDLINE, EMBASE, PubMed, and clinicaltrials.gov was conducted. Studies were included if they were randomised controlled trials of pirfenidone or nintedanib in adult patients with IPF or non-IPF patients, and with extractable data on mortality or decline in forced vital capacity (FVC). Random effects meta-analyses were performed on changes in FVC and where possible on mortality in the selected studies.
RESULTS
13 trials of antifibrotic therapy were pooled in a meta-analysis (with pirfenidone and nintedanib considered together as anti-fibrotic therapy). The change in FVC was expressed as a standardised difference to allow pooling of percentage and absolute changes. The mean effect size in the IPF studies was - 0.305 (SE 0.043) (p < 0.001) and in the non-IPF studies the figures were - 0.307 (SE 0.063) (p < 0.001). There was no evidence of any difference between the two groups for standardised rate of FVC decline (p = 0.979). Pooling IPF and non-IPF showed a significant reduction in mortality, with mean risk ratio of 07.01 in favour of antifibrotic therapy (p = 0.008). A separate analysis restricted to non-IPF did not show a significant reduction in mortality (risk ratio 0.908 (0.547 to 1.508), p = 0.71.
INTERPRETATION
Anti-fibrotic therapy offers protection against the rate of decline in FVC in progressive lung fibrosis, with similar efficacy shown between the two anti-fibrotic agents currently in clinical use. There was no significant difference in efficacy of antifibrotic therapy whether the underlying condition was IPF or non-IPF with progressive fibrosis, supporting the hypothesis of a common pathogenesis. The data in this analysis was insufficient to be confident about a reduction in mortality in non-IPF with anti-fibrotic therapy. Trial Registration PROSPERO, registration number CRD42021266046.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antifibrotic Agents; Cause of Death; Humans; Idiopathic Pulmonary Fibrosis; Indoles; Pulmonary Fibrosis; Pyridones; Treatment Outcome
PubMed: 34895203
DOI: 10.1186/s12890-021-01783-1 -
European Respiratory Review : An... Dec 2018Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis... (Review)
Review
Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs ( rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally.
Topics: Adult; Aged; Diagnosis, Differential; Disease Progression; Female; Humans; Lung; Lung Diseases, Interstitial; Male; Middle Aged; Phenotype; Predictive Value of Tests; Pulmonary Fibrosis; Quality of Life; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome
PubMed: 30578335
DOI: 10.1183/16000617.0076-2018 -
Biomedicine & Pharmacotherapy =... Sep 2022Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies...
BACKGROUND
Pulmonary fibrosis is the deadliest manifestation of connective tissue disease (CTD). Iguratimod (IGU) is a new drug that is used for controlling CTD. Clinical studies have found that IGU has certain advantages in improving lung function and shows great potential for pulmonary fibrosis therapy. However, the specific mechanism is not clear. This study was designed to observe and investigate the therapeutic effects of IGU on bleomycin-induced pulmonary fibrosis and further investigate its underlying mechanism.
METHODS
A mouse model of pulmonary fibrosis was induced by intratracheal injection of bleomycin (BLM). Model mice were randomly assigned to receive different concentrations of IGU. A TGF-β (T)-induced A549 epithelial-mesenchymal transition (EMT) cell model was utilized to investigate the effects of IGU on EMT in vitro. The NLRP3 inflammasome was activated by the costimulation of LPS+ATP (LA) to evaluate the effects of IGU in vitro.
RESULTS
We found that IGU resulted in favourable therapeutic outcomes by affecting inflammatory infiltration and collagen deposition. Additionally, the markers of the BLM-mediated EMT phenotype and NLRP3-activated phenotype in the lung were also attenuated after IGU administration. In vitro experiments, the results confirmed its anti-EMT and anti-NLRP3 inflammasome activation effects.We then found that the anti-lung fibrosis effect of IGU was accompanied by a decrease in reactive oxygen species (ROS) production.
CONCLUSION
IGU can inhibit the EMT process and NLRP3 inflammasome activation and reduce ROS production to ameliorate pulmonary fibrosis, which may provide new insights into the further application of IGU in interstitial pulmonary fibrosis.
Topics: Animals; Bleomycin; Chromones; Epithelial-Mesenchymal Transition; Inflammasomes; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Fibrosis; Reactive Oxygen Species; Sulfonamides
PubMed: 36076570
DOI: 10.1016/j.biopha.2022.113460