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JCI Insight Jul 2023Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling,...
Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc and to investigate pharmacological TAK1 blockade using a potentially novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and it ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.
Topics: Mice; Animals; Fibrosis; Scleroderma, Systemic; Pulmonary Fibrosis; Fibroblasts
PubMed: 37306632
DOI: 10.1172/jci.insight.165358 -
Advanced Drug Delivery Reviews Apr 2018Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary... (Review)
Review
Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3years' post-diagnosis. Treatments for IPF are limited to two FDA approved drugs, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre-clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis.
Topics: Animals; Cell Engineering; Humans; Models, Biological; Pulmonary Fibrosis
PubMed: 29269274
DOI: 10.1016/j.addr.2017.12.013 -
Medicina Clinica Feb 2016
Topics: Acetylcysteine; Azathioprine; Clinical Trials as Topic; Forecasting; Glucocorticoids; Humans; Indoles; Multicenter Studies as Topic; Prognosis; Pulmonary Fibrosis; Pyridones
PubMed: 26238516
DOI: 10.1016/j.medcli.2015.06.002 -
Journal of Cellular and Molecular... Dec 2023To investigate the effect and mechanism of polydatin on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. The lung fibrosis model was induced by BLM. The...
To investigate the effect and mechanism of polydatin on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. The lung fibrosis model was induced by BLM. The contents of TNF-α, LPS, IL-6 and IL-1β in lung tissue, intestine and serum were detected by ELISA. Gut microbiota diversity was detected by 16S rDNA sequencing; R language was used to analyse species composition, α-diversity, β-diversity, species differences and marker species. Mice were fed drinking water mixed with four antibiotics (ampicillin, neomycin, metronidazole, vancomycin; antibiotics, ABx) to build a mouse model of ABx-induced bacterial depletion; and faecal microbiota from different groups were transplanted into BLM-treated or untreated ABx mice. The histopathological changes and collagen I and α-SMA expression were determined. Polydatin effectively reduced the degree of fibrosis in a BLM-induced pulmonary fibrosis mouse model; BLM and/or polydatin affected the abundance of the dominant gut microbiota in mice. Moreover, faecal microbiota transplantation (FMT) from polydatin-treated BLM mice effectively alleviated lung fibrosis in BLM-treated ABx mice compared with FMT from BLM mice. Polydatin can reduce fibrosis and inflammation in a BLM-induced mouse pulmonary fibrosis model. The alteration of gut microbiota by polydatin may be involved in the therapeutic effect.
Topics: Mice; Animals; Pulmonary Fibrosis; Bleomycin; Gastrointestinal Microbiome; Lung; Fibrosis; Anti-Bacterial Agents; Mice, Inbred C57BL
PubMed: 37665061
DOI: 10.1111/jcmm.17937 -
European Journal of Pharmacology Dec 2021Pulmonary fibrosis (PF) is a chronic, progressive heterogeneous disease of lung tissues with poor lung function caused by scar tissue. Due to our limited understanding... (Review)
Review
Pulmonary fibrosis (PF) is a chronic, progressive heterogeneous disease of lung tissues with poor lung function caused by scar tissue. Due to our limited understanding of its mechanism, there is currently no treatment strategy that can prevent the development of PF. In recent years, iron accumulation and mitochondrial damage have been reported to participate in PF, and drugs that reduce iron content and improve mitochondrial function have shown significant efficacy in animal experimental models. Excessive iron leads to mitochondrial impairment, which may be the key cause that results in the dysfunction of various kinds of pulmonary cells and further promotes PF. As an emerging research hotspot, there are few targeted effective therapeutic strategies at present due to limited mechanistic understanding. In this review, the roles of iron homeostasis imbalance and mitochondrial damage in PF are summarized and discussed, highlighting a promising direction for finding truly effective therapeutics for PF.
Topics: Animals; Apoptosis; Homeostasis; Humans; Iron Overload; Mitochondria; Oxidative Stress; Pulmonary Fibrosis
PubMed: 34740581
DOI: 10.1016/j.ejphar.2021.174613 -
Archivos de Bronconeumologia Jan 2018
Topics: Humans; Idiopathic Pulmonary Fibrosis; Precision Medicine; Quality of Life
PubMed: 28757283
DOI: 10.1016/j.arbres.2017.06.020 -
Chest Jan 2016Idiopathic pulmonary fibrosis (IPF) is a devastating and incurable progressive fibrotic lung condition associated with a significant disease burden. In recent years... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a devastating and incurable progressive fibrotic lung condition associated with a significant disease burden. In recent years there has been an exponential increase in the number of preclinical and clinical studies performed in IPF. IPF is defined according to rigid diagnostic criteria; hence, a significant subset of patients with unclassifiable disease has been excluded from these studies. The traditional diagnostic classification of all progressive fibrotic lung diseases uses specific clinical, radiological, and histopathological features to define each condition. However, the considerable heterogeneity within each form of pulmonary fibrosis has raised the possibility of distinct pathophysiological mechanisms culminating in a common phenotype. Thus, the classification of fibrotic lung diseases according to the driving molecular mechanisms rather than specific user-defined histopathological and radiological features could improve several aspects of clinical care. Discoveries from basic science research have defined multiple complex molecular pathways involved in the pathogenesis of pulmonary fibrosis that may provide markers for the molecular endotyping of this disease. In addition, these molecular pathways have revealed potential therapeutic targets. Reclassifying progressive fibrotic lung diseases according to molecular endotypes may allow for more accurate assessment of prognosis and individualized treatment. Furthermore, recent developments that have been applied to a narrow group of patients with IPF may be applicable to those with other progressive fibrotic lung diseases. This review presents the latest developments from translational research in this area and explains how molecular endotyping could revolutionize the diagnosis, stratification, and treatment of pulmonary fibrosis.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Molecular Typing
PubMed: 26356594
DOI: 10.1378/chest.15-1511 -
Archives of Pathology & Laboratory... Mar 2016Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis, can be... (Comparative Study)
Comparative Study Review
CONTEXT
Three distinct patterns of pulmonary fibrosis, including usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis, can be identified on surgical lung biopsies.
OBJECTIVES
To compare the pathologic definitions, clinical and radiographic presentations, etiologies and differential diagnoses, treatments, and prognoses of usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway-centered fibrosis patterns, and to address the challenges and controversies related to pulmonary fibrosis.
DATA SOURCES
Data were derived from published literature and clinical experience.
CONCLUSIONS
Although there may be overlap, identification of the dominant form of fibrosis in a particular case can provide a general category of disease and assist in identifying an etiology.
Topics: Alveolitis, Extrinsic Allergic; Biopsy; Connective Tissue Diseases; Diagnosis, Differential; Humans; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Prognosis; Pulmonary Fibrosis; Radiography; Respiratory Mucosa; Terminology as Topic
PubMed: 26927716
DOI: 10.5858/arpa.2015-0288-SA -
Current Opinion in Pulmonary Medicine Sep 2016Up to twenty percent of patients with sarcoidosis develop pulmonary fibrosis, transforming an often benign disease into a highly morbid and potentially fatal one. We... (Review)
Review
PURPOSE OF REVIEW
Up to twenty percent of patients with sarcoidosis develop pulmonary fibrosis, transforming an often benign disease into a highly morbid and potentially fatal one. We highlight the fibrotic pulmonary sarcoidosis phenotype as an area of intense clinical and translational investigation, review recent developments in treatment, and provide a roadmap for future research in sarcoidosis associated pulmonary fibrosis.
RECENT FINDINGS
Granulomatous inflammation in a lymphatic distribution is the hallmark finding of pulmonary sarcoidosis and the nidus for fibrosis. Recent research demonstrates that fibrotic sarcoidosis begins in the setting of persistent, uncontrolled inflammation, and is aided by pro-fibrotic genetic features and immune responses. Comparison to other fibrotic lung diseases also reveals key features that inform our understanding of common pathways in fibrosis.
SUMMARY
Understanding the mechanisms of fibrotic transformation in sarcoidosis enhances clinical care and facilitates development of novel therapeutic options. The impact of these findings in fibrotic sarcoidosis may be amplified through application to other interstitial lung diseases marked by inflammatory to fibrotic transformation. Important aspects of clinical management of fibrotic sarcoidosis include surveillance for co-morbidities, such as pulmonary hypertension, airway disease, and infection, and assessment for pulmonary disease activity that may benefit from immunosuppression.
Topics: Granuloma; Humans; Pulmonary Fibrosis; Sarcoidosis, Pulmonary
PubMed: 27379967
DOI: 10.1097/MCP.0000000000000301 -
La Radiologia Medica Jul 2016Combined pulmonary fibrosis and emphysema is a relatively newly defined entity, which has been deeply studied in the recent years. Despite the wide numbers of papers on... (Review)
Review
Combined pulmonary fibrosis and emphysema is a relatively newly defined entity, which has been deeply studied in the recent years. Despite the wide numbers of papers on this topic, there are still several open questions about pathogenesis, epidemiology, natural history and prognosis. The diagnosis could be assessed only after HRCT scan as functional tests often result in an underestimation of this syndrome. What radiologists need to know about this syndrome consists in the heterogeneity of appearances: emphysema is mainly paraseptal and fibrotic pattern could be variable, including the variant of airspace enlargement with fibrosis which needs to be differentiated from honeycombing. A special attention must be paid on complications which could worsen the prognosis, such as pulmonary hypertension and lung cancer. Further studies are needed to address if the type of fibrotic pattern as well as fibrosis CT index could be considered as prognostic factors. Thus, the role of radiologists in the management of these patients is crucial as it involves diagnosis, detection of complications and could possible concerns the identification of patients at higher risk.
Topics: Humans; Prognosis; Pulmonary Emphysema; Pulmonary Fibrosis; Risk Factors; Tomography, X-Ray Computed
PubMed: 26892068
DOI: 10.1007/s11547-016-0627-4