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International Journal of Molecular... Aug 2023Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due... (Review)
Review
Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due to oxidative stress and chronic inflammation are central features of lung fibrosis. Chronic cigarette smoking causes oxidative stress and is a major risk factor for lung fibrosis. The objective of this manuscript is to develop an adverse outcome pathway (AOP) that serves as a framework for investigation of the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Based on the weight of evidence, oxidative stress is proposed as a molecular initiating event (MIE) which leads to increased secretion of proinflammatory and profibrotic mediators (key event 1 (KE1)). At the cellular level, these proinflammatory signals induce the recruitment of inflammatory cells (KE2), which in turn, increase fibroblast proliferation and myofibroblast differentiation (KE3). At the tissue level, an increase in extracellular matrix deposition (KE4) subsequently culminates in lung fibrosis, the adverse outcome. We have also defined a new KE relationship between the MIE and KE3. This AOP provides a mechanistic platform to understand and evaluate how persistent oxidative stress from lung injury may develop into lung fibrosis.
Topics: Humans; Pulmonary Fibrosis; Adverse Outcome Pathways; Lung Injury; Lung; Oxidative Stress; Fibrosis
PubMed: 37569865
DOI: 10.3390/ijms241512490 -
Respiratory Research Dec 2023Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive.
METHODS
To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis.
RESULTS
Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pN-WASP). Furthermore, TUFT1 promoted transforming growth factor-β1 (TGF-β1) induced fibroblast activation by increasing nuclear translocation of pN-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes.
CONCLUSIONS
Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.
Topics: Animals; Mice; Bleomycin; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Mice, Inbred C57BL; Stress Fibers; Transforming Growth Factor beta1
PubMed: 38105232
DOI: 10.1186/s12931-023-02633-w -
Biochimica Et Biophysica Acta.... Feb 2024Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic...
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic homeostatic imbalance caused by repetitive injuries of the alveolar epithelium is the potential pathogenesis of IPF. Proteomic analysis identified that Acetyl-CoA synthetase short chain family member 3 (ACSS3) expression was decreased in IPF patients and mice with bleomycin-induced fibrosis. ACSS3 participated in lipid and carbohydrate metabolism. Increased expression of ACSS3 downregulated carnitine palmitoyltransferase 1A (CPT-1A) and resulted in the accumulation of lipid droplets, while enhanced glycolysis which led to an increase in extracellular lactic acid levels in A549 cells. ACSS3 increases the production of succinyl-CoA through propionic acid metabolism, and decreases the generation of acetyl-CoA and ATP in alveolar epithelial cells. Overexpression of Acss3 inhibited the excessive deposition of ECM and attenuated the ground-glass opacity which determined by micro-CT in vivo. In a nutshell, our findings demonstrate that ACSS3 decreased the fatty acid oxidation through CPT1A deficiency and enhanced anaerobic glycolysis, this metabolic reprogramming deactivate the alveolar epithelial cells by lessen mitochondrial fission and fusion, increase of ROS production, suppression of mitophagy, promotion of apoptosis, suggesting that ACSS3 might be potential therapeutic target in pulmonary fibrosis.
Topics: Animals; Humans; Mice; Acetyl Coenzyme A; Epithelial Cells; Homeostasis; Proteomics; Pulmonary Fibrosis; Acetate-CoA Ligase
PubMed: 37979225
DOI: 10.1016/j.bbadis.2023.166960 -
Nature Genetics Nov 2023Joint analysis of single-cell genomics data from diseased tissues and a healthy reference can reveal altered cell states. We investigate whether integrated collections...
Joint analysis of single-cell genomics data from diseased tissues and a healthy reference can reveal altered cell states. We investigate whether integrated collections of data from healthy individuals (cell atlases) are suitable references for disease-state identification and whether matched control samples are needed to minimize false discoveries. We demonstrate that using a reference atlas for latent space learning followed by differential analysis against matched controls leads to improved identification of disease-associated cells, especially with multiple perturbed cell types. Additionally, when an atlas is available, reducing control sample numbers does not increase false discovery rates. Jointly analyzing data from a COVID-19 cohort and a blood cell atlas, we improve detection of infection-related cell states linked to distinct clinical severities. Similarly, we studied disease states in pulmonary fibrosis using a healthy lung atlas, characterizing two distinct aberrant basal states. Our analysis provides guidelines for designing disease cohort studies and optimizing cell atlas use.
Topics: Humans; Genomics; Pulmonary Fibrosis; Single-Cell Analysis
PubMed: 37828140
DOI: 10.1038/s41588-023-01523-7 -
Canadian Respiratory Journal 2023. Dysregulation of epithelial-mesenchymal transition (EMT) in the airway epithelium is associated with airway remodeling and the progression of pulmonary fibrosis. Many... (Review)
Review
. Dysregulation of epithelial-mesenchymal transition (EMT) in the airway epithelium is associated with airway remodeling and the progression of pulmonary fibrosis. Many treatments have been shown to inhibit airway remodeling and pulmonary fibrosis progression in asthma and chronic obstructive pulmonary disease (COPD) by regulating EMT and have few side effects. This review aimed to describe the development of airway remodeling through the EMT pathway, as well as the potential therapeutic targets in these pathways. Furthermore, this study aimed to review the current research on drugs to treat airway remodeling and their effects on the EMT pathway. . The dysregulation of EMT was associated with airway remodeling in various respiratory diseases. The cytokines released during inflammation may induce EMT and subsequent airway remodeling. Various drugs, including herbal formulations, specific herbal compounds, cytokines, amino acid or protein inhibitors, microRNAs, and vitamins, may suppress airway remodeling by inhibiting EMT-related pathways.
Topics: Humans; Pulmonary Fibrosis; Airway Remodeling; Asthma; Epithelial-Mesenchymal Transition; Cytokines
PubMed: 38074219
DOI: 10.1155/2023/3291957 -
Frontiers in Endocrinology 2024At present, pulmonary fibrosis (PF) is a prevalent and irreversible lung disease with limited treatment options, and idiopathic pulmonary fibrosis (IPF) is one of its... (Review)
Review
At present, pulmonary fibrosis (PF) is a prevalent and irreversible lung disease with limited treatment options, and idiopathic pulmonary fibrosis (IPF) is one of its most common forms. Recent research has highlighted PF as a metabolic-related disease, including dysregulated iron, mitochondria, lipid, and glucose homeostasis. Systematic reports on the regulatory roles of glucose metabolism in PF are rare. This study explores the intricate relationships and signaling pathways between glucose metabolic processes and PF, delving into how key factors involved in glucose metabolism regulate PF progression, and the interplay between them. Specifically, we examined various enzymes, such as hexokinase (HK), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), pyruvate kinase (PK), and lactate dehydrogenase (LDH), illustrating their regulatory roles in PF. It highlights the significance of lactate, alongside the role of pyruvate dehydrogenase kinase (PDK) and glucose transporters (GLUTs) in modulating pulmonary fibrosis and glucose metabolism. Additionally, critical regulatory factors such as transforming growth factor-beta (TGF-β), interleukin-1 beta (IL-1β), and hypoxia-inducible factor 1 subunit alpha (HIF-1α) were discussed, demonstrating their impact on both PF and glucose metabolic pathways. It underscores the pivotal role of AMP-activated protein kinase (AMPK) in this interplay, drawing connections between diabetes mellitus, insulin, insulin-like growth factors, and peroxisome proliferator-activated receptor gamma (PPARγ) with PF. This study emphasizes the role of key enzymes, regulators, and glucose transporters in fibrogenesis, suggesting the potential of targeting glucose metabolism for the clinical diagnosis and treatment of PF, and proposing new promising avenues for future research and therapeutic development.
Topics: Humans; Glycolysis; Glucose; Pulmonary Fibrosis; Animals; Signal Transduction
PubMed: 38854692
DOI: 10.3389/fendo.2024.1379521 -
Respiratory Research Feb 2024Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. Circular RNAs (circRNAs) have emerged as a novel class of... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. Circular RNAs (circRNAs) have emerged as a novel class of non-coding RNAs with diverse functions in cellular processes. This review paper aims to explore the potential involvement of circRNAs in the pathogenesis of IPF and their diagnostic and therapeutic implications. We begin by providing an overview of the epidemiology and risk factors associated with IPF, followed by a discussion of the pathophysiology underlying this complex disease. Subsequently, we delve into the history, types, biogenesis, and functions of circRNAs and then emphasize their regulatory roles in the pathogenesis of IPF. Furthermore, we examine the current methodologies for detecting circRNAs and explore their diagnostic applications in IPF. Finally, we discuss the potential utility of circRNAs in the treatment of IPF. In conclusion, circRNAs hold great promise as novel biomarkers and therapeutic targets in the management of IPF.
Topics: Humans; RNA, Circular; Idiopathic Pulmonary Fibrosis; Biomarkers
PubMed: 38321530
DOI: 10.1186/s12931-024-02716-2 -
Human Vaccines & Immunotherapeutics Dec 2024Mimotope, a kind of peptide vaccine, is developed to bind natural receptor and inhibit the downstream signaling. We have demonstrated that the vaccination of Tocilizumab...
Mimotope, a kind of peptide vaccine, is developed to bind natural receptor and inhibit the downstream signaling. We have demonstrated that the vaccination of Tocilizumab mimotopes could alleviate the renal fibrosis by interfering with both IL-6 and ferroptosis signaling. However, the effect of the vaccination of Tocilizumab mimotopes on the fibroblast was not investigated in previous study. Thus, we sought to explore the changes in the fibroblast induced by the Tocilizumab mimotopes vaccination. Bleomycin instillation was performed to construct the pulmonary fibrosis model after the immunization of Tocilizumab mimotopes. Lung histological analysis showed that the Tocilizumab mimotopes could significantly reduce the maladaptive repairment and abnormal remodeling. Immunoblotting assay and fluorescence staining showed that Immunization with the Tocilizumab mimotopes reduces the accumulation of fibrosis-related proteins. High level of lipid peroxidation product was observed in the animal model, while the Tocilizumab mimotopes vaccination could reduce the generation of lipid peroxidation product. Mechanism analysis further showed that Nrf-2 signaling, but not GPX-4 and FSP-1 signaling, was upregulated, and reduced the lipid peroxidation. Our results revealed that in the BLM-induced pulmonary fibrosis, high level of lipid peroxidation product was significantly accumulation in the lung tissues, which might lead to the occurrence of ferroptosis. The IL-6 pathway block therapy could inhibit lipid peroxidation product generation in the lung tissues by upregulating the Nrf-2 signaling, and further alleviate the pulmonary fibrosis.
Topics: Animals; Pulmonary Fibrosis; Interleukin-6; Bleomycin; Lung; Vaccination; Antibodies, Monoclonal, Humanized
PubMed: 38408907
DOI: 10.1080/21645515.2024.2319965 -
BMC Pulmonary Medicine May 2024Since COVID-19 became a global epidemic disease in 2019, pulmonary fibrosis (PF) has become more prevalent among persons with severe infections, with IPF being the most...
BACKGROUND
Since COVID-19 became a global epidemic disease in 2019, pulmonary fibrosis (PF) has become more prevalent among persons with severe infections, with IPF being the most prevalent form. In traditional Chinese medicine, various disorders are treated using Sinomenine (SIN). The SIN's strategy for PF defense is unclear.
METHODS
Bleomycin (BLM) was used to induce PF, after which inflammatory factors, lung histological alterations, and the TGF-/Smad signaling pathway were assessed. By administering various dosages of SIN and the TGF- receptor inhibitor SB-431,542 to human embryonic lung fibroblasts (HFL-1) and A549 cells, we were able to examine proliferation and migration as well as the signaling molecules implicated in Epithelial-Mesenchymal Transition (EMT) and Extra-Cellular Matrix (ECM).
RESULTS
In vivo, SIN reduced the pathological changes in the lung tissue induced by BLM, reduced the abnormal expression of inflammatory cytokines, and improved the weight and survival rate of mice. In vitro, SIN inhibited the migration and proliferation by inhibiting TGF-β1/Smad3, PI3K/Akt, and NF-κB pathways, prevented the myofibroblasts (FMT) of HFL-1, reversed the EMT of A549 cells, restored the balance of matrix metalloenzymes, and reduced the expression of ECM proteins.
CONCLUSION
SIN attenuated PF by down-regulating TGF-β/Smad3, PI3K/Akt, and NF-κB signaling pathways, being a potential effective drug in the treatment of PF.
Topics: Animals; Humans; Male; Mice; A549 Cells; Bleomycin; Cell Movement; Cell Proliferation; Disease Models, Animal; Down-Regulation; Epithelial-Mesenchymal Transition; Lung; Mice, Inbred C57BL; Morphinans; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta1
PubMed: 38730387
DOI: 10.1186/s12890-024-03050-5 -
JCI Insight Nov 2023Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition...
Aberrant fibroblast function plays a key role in the pathogenesis of idiopathic pulmonary fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor α-positive (Pdgfra+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used single-cell RNA-Seq (scRNA-Seq) technology and PdgfraGFP lineage tracing to generate a transcriptomic profile of Pdgfra+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating 11 unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured Pdgfra+ fibroblast-supported organoids were morphologically distinct from those cultured with normal fibroblasts, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured Pdgfra+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.
Topics: Animals; Mice; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Lung Injury; Receptor Protein-Tyrosine Kinases
PubMed: 37824216
DOI: 10.1172/jci.insight.164380