RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by pulmonary fibroblast overactivation, resulting in the accumulation of abnormal extracellular matrix and lung parenchymal damage. Although the pathogenesis of IPF remains unclear, aging was proposed as the most prominent nongenetic risk factor. Propionate metabolism undergoes reprogramming in the aging population, leading to the accumulation of the by-product methylmalonic acid (MMA). This study aimed to explore alterations in propionate metabolism in IPF and the impact of the by-product MMA on pulmonary fibrosis. It revealed alterations in the expression of enzymes involved in propionate metabolism within IPF lung tissues, characterized by an increase in propionyl-CoA carboxylase and methylmalonyl-CoA epimerase expression, and a decrease in methylmalonyl-CoA mutase expression. Knockdown of methylmalonyl-CoA mutase, the key enzyme in propionate metabolism, induced a profibrotic phenotype and activated co-cultured fibroblasts in A549 cells. MMA exacerbated bleomycin-induced mouse lung fibrosis and induced a profibrotic phenotype in both epithelial cells and fibroblasts through activation of the canonical transforming growth factor-ß/Smad pathway. Overall, these findings unveil an alteration of propionate metabolism in IPF, leading to MMA accumulation, thus exacerbating lung fibrosis through promoting profibrotic phenotypic transitions via the canonical transforming growth factor-ß/Smad signaling pathway.
Asunto(s)
Envejecimiento , Fibrosis Pulmonar Idiopática , Ácido Metilmalónico , Animales , Humanos , Ratones , Ácido Metilmalónico/metabolismo , Envejecimiento/metabolismo , Envejecimiento/patología , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/inducido químicamente , Masculino , Fibroblastos/metabolismo , Fibroblastos/patología , Femenino , Ratones Endogámicos C57BL , Anciano , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/inducido químicamente , Persona de Mediana Edad , Células A549 , Bleomicina/efectos adversos , Pulmón/patología , Pulmón/metabolismoRESUMEN
Considerable progress has been made in understanding the function of alveolar epithelial cells in a quiescent state and regeneration mechanism after lung injury. Lung injury occurs commonly from severe viral and bacterial infections, inhalation lung injury, and indirect injury sepsis. A series of pathological mechanisms caused by excessive injury, such as apoptosis, autophagy, senescence, and ferroptosis, have been studied. Recovery from lung injury requires the integrity of the alveolar epithelial cell barrier and the realization of gas exchange function. Regeneration mechanisms include the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and proteins. While alveoli are damaged, alveolar type II (AT2) cells proliferate and differentiate into alveolar type I (AT1) cells to repair the damaged alveolar epithelial layer. Alveolar epithelial cells are surrounded by various cells, such as fibroblasts, endothelial cells, and various immune cells, which affect the proliferation and differentiation of AT2 cells through paracrine during alveolar regeneration. Besides, airway epithelial cells also contribute to the repair and regeneration process of alveolar epithelium. In this review, we mainly discuss the participation of epithelial progenitor cells and various niche cells involving several signaling pathways and transcription factors.
Asunto(s)
Células Epiteliales Alveolares , Lesión Pulmonar , Regeneración , Humanos , Regeneración/fisiología , Animales , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Células Madre/metabolismo , Células Madre/fisiología , Alveolos Pulmonares/patología , Alveolos Pulmonares/metabolismo , Transducción de Señal , Diferenciación CelularRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with an abnormal accumulation of fibrotic tissue in the lung parenchyma and elevated glycolysis level in associated cells without effective therapy options. Lactate accumulation in pulmonary fibrotic tissue is a significant factor aggravating IPF development, but the main mechanism regulating glycolysis needs further investigation. In this study, lung fibrosis model was induced by bleomycin (BLM) intratracheally in female C57BL/6 mice. The changes of lactate level and fibrotic markers were detected. For in vitro studies, cell lines of alveolar epithelial cell and lung fibroblast cell were stimulated with TGF-ß1 and BLM respectively, to detect changes in their fibrotic properties. The function of lactate accumulation on facilitating fibrosis was verified. We demonstrated that BLM-induced pulmonary fibrosis is accompanied by lactate accumulation owing to glycolysis upregulation. Significantly high PDK1 expression in lung fibrotic tissue promotes glycolysis. Moreover, PDK1 stimulated trans-differentiation of lung fibroblasts and epithelial-mesenchymal transition (EMT) of alveolar epithelial cells. Furthermore, phosphorylated Akt2 activated PDK1 to cause pulmonary fibrosis and inhibitors of Akt2 and PDK1 could suppress fibrotic process. This study is the first to consider PDK1 facilitated lactate accumulation through glycolysis as a vital factor in pulmonary fibrosis and could be initiated by Akt2. We concluded that the pro-fibrotic properties of PDK1 are associated with Akt2 phosphorylation and thus provide new potential therapeutic targets for pulmonary fibrosis.
Asunto(s)
Fibrosis Pulmonar Idiopática , Ácido Láctico , Femenino , Ratones , Animales , Ratones Endogámicos C57BL , Transducción de Señal , Fibrosis Pulmonar Idiopática/inducido químicamente , Células Epiteliales Alveolares , Bleomicina/toxicidad , Proteínas Proto-Oncogénicas c-aktRESUMEN
The heterogeneity of idiopathic pulmonary fibrosis (IPF) limits its diagnosis and treatment. The association between the pathophysiological features and the serum protein signatures of IPF currently remains unclear. The present study analyzed the specific proteins and patterns associated with the clinical parameters of IPF based on a serum proteomic dataset by data-independent acquisition using MS. Differentiated proteins in sera distinguished patients with IPF into three subgroups in signal pathways and overall survival. Aging-associated signatures by weighted gene correlation network analysis coincidently provided clear and direct evidence that aging is a critical risk factor for IPF rather than a single biomarker. Expression of LDHA and CCT6A, which was associated with glucose metabolic reprogramming, was correlated with high serum lactic acid content in patients with IPF. Cross-model analysis and machine learning showed that a combinatorial biomarker accurately distinguished patients with IPF from healthy individuals with an area under the curve of 0.848 (95% CI = 0.684-0.941) and validated from another cohort and ELISA assay. This serum proteomic profile provides rigorous evidence that enables an understanding of the heterogeneity of IPF and protein alterations that could help in its diagnosis and treatment decisions.
Asunto(s)
Fibrosis Pulmonar Idiopática , Proteómica , Humanos , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Proteínas Sanguíneas , Biomarcadores , Chaperonina con TCP-1RESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung diseases, which mainly existed in middle-aged and elderly people. The accumulation of reactive oxygen species (ROS) is a common characteristic of IPF. Previous research also shown that lactate levels can be abnormally elevated in IPF patients. Emerging evidence suggested a relationship between lactate and ROS in IPF which needs further elucidation. In this article, we utilized a mouse model of BLM-induced pulmonary fibrosis to detect alterations in ROS levels and other indicators associated with fibrosis. Lactate could induce mitochondrial fragmentation by modulating expression and activity of DRP1 and ERK. Moreover, Increased ROS promoted P65 translocation into nucleus, leading to expression of lung fibrotic markers. Finally, Ulixertinib, Mdivi-1 and Mito-TEMPO, which were inhibitor activity of ERK, DRP1 and mtROS, respectively, could effectively prevented mitochondrial damage and production of ROS and eventually alleviate pulmonary fibrosis. Taken together, these findings suggested that lactate could promote lung fibrosis by increasing mitochondrial fission-derived ROS via ERK/DRP1 signaling, which may provide novel therapeutic solutions for IPF.
Asunto(s)
Dinaminas , Ratones Endogámicos C57BL , Dinámicas Mitocondriales , Especies Reactivas de Oxígeno , Animales , Especies Reactivas de Oxígeno/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Dinaminas/metabolismo , Bleomicina , Transducción de Señal , Ácido Láctico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Mitocondrias/metabolismo , Masculino , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Ratones , HumanosRESUMEN
BACKGROUND: Abnormal lipid metabolism has recently been reported as a crucial signature of idiopathic pulmonary fibrosis (IPF). However, the origin and biological function of the lipid and possible mechanisms of increased lipid content in the pathogenesis of IPF remains undetermined. METHODS: Oil-red staining and immunofluorescence analysis were used to detect lipid accumulation in mouse lung fibrosis frozen sections, Bleomycin-treated human type II alveolar epithelial cells (AECIIs) and lung fibroblast. Untargeted Lipid omics analysis was applied to investigate differential lipid species and identified LysoPC was utilized to treat human lung fibroblasts and mice. Microarray and single-cell RNA expression data sets identified lipid metabolism-related differentially expressed genes. Gain of function experiment was used to study the function of 3-hydroxy-3-methylglutaryl-Coa Synthase 2 (HMGCS2) in regulating AECIIs lipid metabolism. Mice with AECII-HMGCS2 high were established by intratracheally delivering HBAAV2/6-SFTPC- HMGCS2 adeno-associated virus. Western blot, Co-immunoprecipitation, immunofluorescence, site-directed mutation and flow cytometry were utilized to investigate the mechanisms of HMGCS2-mediated lipid metabolism in AECIIs. RESULTS: Injured AECIIs were the primary source of accumulated lipids in response to Bleomycin stimulation. LysoPCs released by injured AECIIs could activate lung fibroblasts, thus promoting the progression of pulmonary fibrosis. Mechanistically, HMGCS2 was decreased explicitly in AECIIs and ectopic expression of HMGCS2 in AECIIs using the AAV system significantly alleviated experimental mouse lung fibrosis progression via modulating lipid degradation in AECIIs through promoting CPT1A and CPT2 expression by interacting with PPARα. CONCLUSIONS: These data unveiled a novel etiological mechanism of HMGCS2-mediated AECII lipid metabolism in the genesis and development of pulmonary fibrosis and provided a novel target for clinical intervention.
Asunto(s)
Regulación hacia Abajo , Fibroblastos , Hidroximetilglutaril-CoA Sintasa , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Animales , Humanos , Masculino , Ratones , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Bleomicina/toxicidad , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patología , Hidroximetilglutaril-CoA Sintasa/metabolismo , Hidroximetilglutaril-CoA Sintasa/genética , Hidroximetilglutaril-CoA Sintasa/biosíntesis , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/genética , Metabolismo de los Lípidos/fisiología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/genéticaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal, and aging-associated interstitial lung disease with a poor prognosis and limited treatment options, while the pathogenesis remains elusive. In this study, we found that the expression of nuclear receptor subfamily 2 group F member 2 (NR2F2), a member of the steroid thyroid hormone superfamily of nuclear receptors, was reduced in both IPF and bleomycin-induced fibrotic lungs, markedly in bleomycin-induced senescent epithelial cells. Inhibition of NR2F2 expression increased the expression of senescence markers such as p21 and p16 in lung epithelial cells, and activated fibroblasts through epithelial-mesenchymal crosstalk, inversely overexpression of NR2F2 alleviated bleomycin-induced epithelial cell senescence and inhibited fibroblast activation. Subsequent mechanistic studies revealed that overexpression of NR2F2 alleviated DNA damage in lung epithelial cells and inhibited cell senescence. Adenovirus-mediated Nr2f2 overexpression attenuated bleomycin-induced lung fibrosis and cell senescence in mice. In summary, these data demonstrate that NR2F2 is involved in lung epithelial cell senescence, and targeting NR2F2 may be a promising therapeutic approach against lung cell senescence and fibrosis.
Asunto(s)
Senescencia Celular , Fibrosis Pulmonar Idiopática , Animales , Ratones , Bleomicina/efectos adversos , Células Epiteliales/metabolismo , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Pulmón/metabolismoRESUMEN
BACKGROUND: Patients with chronic liver disease were found nearly all to have liver fibrosis, which is characterized by excess accumulation of extracellular matrix (ECM) proteins. While ECM accumulation can prevent liver infection and injury, it can destroy normal liver function and architecture. miRNA's own regulation was involved in DNA methylation change. The purpose of this study is to detect DNA methylation landscape of miRNAs genes in mice liver fibrosis tissues. METHODS: Male mice (10-12 weeks) were injected CCl4 from abdominal cavity to induced liver fibrosis. 850 K BeadChips were used to examine DNA methylation change in whole genome. The methylation change of 16 CpG dinucleotides located in promoter regions of 4 miRNA genes were detected by bisulfite sequencing polymerase chain reaction (BSP) to verify chip data accuracy, and these 4 miRNA genes' expressions were detected by RT-qPCR methods. RESULTS: There are 769 differential methylation sites (DMS) in total between fibrotic liver tissue and normal mice liver tissue, which were related with 148 different miRNA genes. Chips array data were confirmed by bisulfite sequencing polymerase chain reaction (R = 0.953; P < 0.01). GO analysis of the target genes of 2 miRNA revealed that protein binding, cytoplasm and chromatin binding activity were commonly enriched; KEGG pathway enrichment analysis displayed that TGF-beta signaling pathway was commonly enriched. CONCLUSION: The DNA of 148 miRNA genes was found to have methylation change in liver fibrosis tissue. These discoveries in miRNA genes are beneficial to future miRNA function research in liver fibrosis.
Asunto(s)
Metilación de ADN , MicroARNs , Sulfitos , Humanos , Masculino , Ratones , Animales , Metilación de ADN/genética , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , ADN/metabolismoRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial-mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of ß-catenin. We concluded that the miR-29bâTRIOBP-TRIO-ß-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis.
Asunto(s)
Fibrosis Pulmonar Idiopática , MicroARNs , Animales , Humanos , Ratones , beta Catenina/genética , beta Catenina/metabolismo , Fibroblastos/metabolismo , Fibrosis , Fibrosis Pulmonar Idiopática/patología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF), an interstitial lung disease, is characterized by the exacerbation of progressive pulmonary fibrosis (PF). IPF primarily affects older individuals and can lead to respiratory failure. This study aimed to assess the effects of triiodothyronine (T3) treatment on the lung microbiome of mice with PF. METHODS: Mice were perfused with bleomycin (BLM) to establish a PF model. Using a randomized design, 40 female specific pathogen-free (SPF) C57BL6/N mice were divided into four groups: saline, saline + T3, BLM, and BLM + T3. Histological morphology was assessed through Hematoxylin and Eosin staining as well as Masson's Trichrome staining. For the identification of lung bacteria, 16S rRNA gene sequencing was employed. An Enzyme-Linked Immunosorbent Assay was used to measure total T3 (TT3), free T3 (FT3, and reverse T3 (rT3) levels in the peripheral serum. RESULTS: T3 treatment ameliorated BLM-induced lung fibrosis and structural damage. The microbiome experienced a decrease in the abundance of Proteobacteria, Bacteroides, and Actinomycetes and an increase in the abundance of Firmicutes when exposed to BLM; however, T3 treatment reversed this effect. The four groups showed no significant difference in alpha microbiome diversity (P > 0.05). Serum concentrations of TT3 and FT3 were positively correlated with microbiome abundance (P < 0.05). Administration of T3 enhanced the microbiota in PF without affecting the diversity and biological functions of the microbiome (P > 0.05). CONCLUSION: The administration of T3 demonstrated a favorable impact on the lung microbiota of mice afflicted with PF, thereby partially substantiating the potential role of T3 as a therapeutic agent in the management of PF.
Asunto(s)
Bleomicina , Modelos Animales de Enfermedad , Pulmón , Ratones Endogámicos C57BL , Microbiota , ARN Ribosómico 16S , Triyodotironina , Animales , Ratones , Triyodotironina/sangre , Triyodotironina/farmacología , Microbiota/efectos de los fármacos , Pulmón/patología , Pulmón/microbiología , Femenino , ARN Ribosómico 16S/genética , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/microbiología , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/microbiologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and irreversible interstitial lung disease with unknown cause. To explore the role and regulatory mechanism of leucine-rich repeat-containing protein 15 (LRRC15) in IPF, bleomycin (BLM)-induced pulmonary fibrosis in mouse and A549 cells were constructed, and the expression of LRRC15 were detected. Then, MTT, GFP-RFP-LC3 dual fluorescent labeling system and Western blotting were used to investigate the effects of LRRC15 on cell activity and autophagy after transfection of siLRRC15, respectively. The results indicated that the expression of LRRC15 was significantly increased after the BLM treatment in mouse lung tissue and A549 cells. The designed and synthesized siLRRC15 followed by transfection into A549 cells resulted in a dramatic reduction in LRRC15 expression and partially restored the cell damage induced by BLM. Moreover, the expression of LC3-II and P62 were up-regulated, the amount of autophagosome were increased by GFP-RFP-LC3 dual fluorescent labeling assay after BLM treatment. Meanwhile, this study also showed that the key autophagy proteins LC3-II, ATG5 and ATG7 were up-regulated, P62 was down-regulated and autophagic flux were enhanced after further treatment of A549 cells with siLRRC15. The above findings suggest that LRRC15 is an indicator of epithelial cell damage and may participate in the regulation of fibrosis through autophagy mechanism in IPF. This study provides necessary theoretical basis for further elucidating the mechanism of IPF.
Asunto(s)
Autofagia , Bleomicina , Animales , Humanos , Masculino , Ratones , Células A549 , Autofagia/efectos de los fármacos , Bleomicina/farmacología , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/genética , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismoRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive fatal interstitial lung disease without an effective cure. Herein, we explore the role of 3,5,3'-triiodothyronine (T3) administration on lung alveolar regeneration and fibrosis at the single-cell level. T3 supplementation significantly altered the gene expression in fibrotic lung tissues. Immune cells were rapidly recruited into the lung after the injury; there were much more M2 macrophages than M1 macrophages in the lungs of bleomycin-treated mice; and M1 macrophages increased slightly, whereas M2 macrophages were significantly reduced after T3 treatment. T3 enhanced the resolution of pulmonary fibrosis by promoting the differentiation of Krt8+ transitional alveolar type II epithelial cells into alveolar type I epithelial cells and inhibiting fibroblast activation and extracellular matrix production potentially by regulation of Nr2f2. In addition, T3 regulated the crosstalk of macrophages with fibroblasts, and the Pros1-Axl signaling axis significantly facilitated the attenuation of fibrosis. The findings demonstrate that administration of a thyroid hormone promotes alveolar regeneration and resolves fibrosis mainly by regulation of the cellular state and cell-cell communication of alveolar epithelial cells, macrophages, and fibroblasts in mouse lungs in comprehensive ways.
Asunto(s)
Fibrosis Pulmonar Idiopática , Ratones , Animales , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/patología , Fibrosis , Bleomicina/farmacología , Fibroblastos/metabolismo , Hormonas Tiroideas/metabolismo , Análisis de Secuencia de ARNRESUMEN
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 (pY256N-WASP). Furthermore, TUFT1 promoted transforming growth factor-ß1 (TGF-ß1) induced fibroblast activation by increasing nuclear translocation of pY256N-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.
Asunto(s)
Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Animales , Ratones , Bleomicina/toxicidad , Fibroblastos/metabolismo , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/metabolismo , Enfermedades Pulmonares Intersticiales/metabolismo , Ratones Endogámicos C57BL , Fibras de Estrés/metabolismo , Factor de Crecimiento Transformador beta1/farmacologíaRESUMEN
BACKGROUND: Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear. METHODS: To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively. RESULTS: In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model. CONCLUSION: MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.
Asunto(s)
Células Endoteliales , Fibrosis Pulmonar Idiopática , Metaloproteinasas de la Matriz Secretadas , Animales , Humanos , Ratones , Bleomicina/efectos adversos , Bosentán/metabolismo , Bosentán/uso terapéutico , Células Endoteliales/patología , Transición Epitelial-Mesenquimal , Fibrosis Pulmonar Idiopática/patología , Pulmón/metabolismo , Monocitos , Metaloproteinasas de la Matriz Secretadas/metabolismoRESUMEN
Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by myofibroblast abnormal activation and extracellular matrix deposition. However, the pathogenesis of PF remains unclear, and treatment options are limited. Epidemiological studies have shown that the average age of PF patients is estimated to be over 65 years, and the incidence of the disease increases with age. Therefore, PF is considered an age-related disease. A preliminary study on PF patients demonstrated that the combination therapy of the anti-senescence drugs dasatinib and quercetin improved physical functional indicators. Given the global aging population and the role of cellular senescence in tissue and organ aging, understanding the impact of cellular senescence on PF is of growing interest. This article systematically summarizes the causes and signaling pathways of cellular senescence in PF. It also objectively analyzes the impact of senescence in AECs and fibroblasts on PF development. Furthermore, potential intervention methods targeting cellular senescence in PF treatment are discussed. This review not only provides a strong theoretical foundation for understanding and manipulating cellular senescence, developing new therapies to improve age-related diseases, and extending a healthy lifespan but also offers hope for reversing the toxicity caused by the massive accumulation of senescence cells in humans.
Asunto(s)
Fibrosis Pulmonar Idiopática , Humanos , Caballos , Animales , Anciano , Fibrosis Pulmonar Idiopática/metabolismo , Senescencia Celular/fisiología , Envejecimiento , Quercetina/uso terapéutico , Transducción de Señal , Fibrosis , Pulmón/patologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by excessive deposition of fibrotic connective tissue in the lungs. Emerging evidence suggests that metabolic alterations, particularly glycolysis reprogramming, play a crucial role in the pathogenesis of IPF. Lactate, once considered a metabolic waste product, is now recognized as a signaling molecule involved in various cellular processes. In the context of IPF, lactate has been shown to promote fibroblast activation, myofibroblast differentiation, and extracellular matrix remodeling. Furthermore, lactate can modulate immune responses and contribute to the pro-inflammatory microenvironment observed in IPF. In addition, lactate has been implicated in the crosstalk between different cell types involved in IPF; it can influence cell-cell communication, cytokine production, and the activation of profibrotic signaling pathways. This review aims to summarize the current research progress on the role of glycolytic reprogramming and lactate in IPF and its potential implications to clarify the role of lactate in IPF and to provide a reference and direction for future research. In conclusion, elucidating the intricate interplay between lactate metabolism and fibrotic processes may lead to the development of innovative therapeutic strategies for IPF.
Asunto(s)
Fibrosis Pulmonar Idiopática , Ácido Láctico , Humanos , Comunicación Celular , Glucólisis , PulmónRESUMEN
The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the extracellular matrix (ECM). However, the pathogenesis of PF is still indistinct. In recent years, many researchers have realized that endothelial cells had a crucial role in the development of PF. Studies have demonstrated that about 16% of the fibroblasts in the lung tissue of fibrotic mice were derived from endothelial cells. Endothelial cells transdifferentiated into mesenchymal cells via the endothelial-mesenchymal transition (E(nd)MT), leading to the excessive proliferation of endothelial-derived mesenchymal cells and the accumulation of fibroblasts and ECM. This suggested that endothelial cells, a significant component of the vascular barrier, played an essential role in PF. Herein, this review discusses E(nd)MT and its contribution to the activation of other cells in PF, which could provide new ideas for further understanding the source and activation mechanism of fibroblasts and the pathogenesis of PF.
Asunto(s)
Fibrosis Pulmonar , Ratones , Animales , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/patología , Células Endoteliales/patología , Fibrosis , Fibroblastos/patología , Miofibroblastos/patología , Factores de RiesgoRESUMEN
BACKGROUND: Zinc finger protein 143(ZNF143), a member of the Krüppel C2H2-type zinc finger protein family, is strongly associated with cell cycle regulation and cancer development. A recent study suggested that ZNF143 plays as a transcriptional activator that promotes hepatocellular cancer (HCC) cell proliferation and cell cycle transition. However, the exact biological role of ZNF143 in liver regeneration and normal liver cell proliferation has not yet been investigated. METHODS: In our study, we constructed a stable rat liver cell line (BRL-3A) overexpressing ZNF143 and then integrated RNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag) data to identify the mechanism underlying differential gene expression. RESULTS: Our results show that ZNF143 expression is upregulated during the proliferation phase of liver regeneration after 2/3 partial hepatectomy (PH). The cell counting kit-8 (CCK-8) assay, EdU staining and RNA-seq data analyses revealed that ZNF143 overexpression (OE) significantly inhibited BRL-3A cell proliferation and cell cycle progression. We then performed CUT&Tag assays and found that approximately 10% of ZNF143-binding sites (BSs) were significantly changed genome-wide by ZNF143 OE. However, CCCTC-binding factor (CTCF) binding to chromatin was not affected. Interestingly, the integration analysis of RNA-seq and CUT&Tag data showed that some of genes affected by ZNF143 differential BSs are in the center of each gene regulation module. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that these genes are critical in the maintenance of cell identity. CONCLUSION: These results indicated that the expression level of ZNF143 in the liver is important for the maintenance of cell identity. ZNF143 plays different roles in HCC and normal liver cells and may be considered as a potential therapeutic target in liver disease.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Proliferación Celular/genética , Ratas , Transactivadores/genética , Transactivadores/metabolismoRESUMEN
Microplastics have become a worldwide pollutant, widely discovered in soil, air and aquatic environment. Microplastics have been found in habitats where crayfish (Procambarus clarkii) cultivated, but the impact of microplastics on crayfish remains unclear. In this study, after 21-day dietary exposure, polyethylene (PE) particles were found to accumulate in intestine, hepatopancreas, gills and hemolymph of crayfish. Furthermore, PE particles can still be detected in these tissues after a 7-day depuration in clean water. PE retained in these tissues caused oxidative stress responses, as indicated by the change of oxidative-stress-related index, such as the increase of H2O2 level and SOD activity. PE exposure also caused hemocytic encapsulation in crayfish hepatopancreas and increase of mucus secretion in intestine. Moreover, PE exposure affected the microbiota balance in crayfish, by reducing the total microbiota abundance and altering the proportions of many bacterial families. Interestingly, results showed that PE exposure led to of lower numbers of hemocytes and declination of phenoloxidase activity. Finally, PE exposure induced the expression of immune-related genes, including transcription factors and antimicrobial peptides. Taken these together, we conclude that PE microplastics exert considerable toxic effects on crayfish and are a potential threat to crayfish aquaculture and consumption. This study provides basic toxicological data toward quantifying and illuminating the impact of PE microplastics on freshwater animals.
Asunto(s)
Microbiota , Contaminantes Químicos del Agua , Animales , Astacoidea/genética , Disbiosis , Peróxido de Hidrógeno/metabolismo , Microplásticos , Estrés Oxidativo , Plásticos , Polietileno , Contaminantes Químicos del Agua/toxicidadRESUMEN
Fat storage-inducing transmembrane proteins (FITMs) were initially identified in 2007 as members of a conserved endoplasmic reticulum (ER) resident transmembrane protein gene family, and were found to be involved in lipid droplet (LD) formation. Recently, several studies have further demonstrated that the ability of FITMs to directly bind to triglyceride and diacylglycerol, and the diphosphatase activity of hydrolyzing fatty acyl-CoA, might enable FITMs to maintain the formation of lipid droplets, engage in lipid metabolism, and protect against cellular stress. Based on the distribution of FITMs in tissues and their important roles in lipid droplet biology and lipid metabolism, it was discovered that FITMs were closely related to muscle development, adipocyte differentiation, and energy metabolism. Accordingly, the abnormal expression of FITMs was not only associated with type 2 diabetes and lipodystrophy, but also with cardiac disease and several types of cancer. This study reviews the structure, distribution, expression regulation, and functionality of FITMs and their potential relationships with various metabolic diseases, hoping to provide inspiration for fruitful research directions and applications of FITM proteins. Moreover, this review will provide an important theoretical basis for the application of FITMs in the diagnosis and treatment of related diseases.