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1.
Front Immunol ; 12: 636118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854506

RESUMO

Following respiratory viral infections or local immunizations, lung resident-memory T cells (TRM) of the CD8 lineage provide protection against the same pathogen or related pathogens with cross-reactive T cell epitopes. Yet, it is now clear that, if homeostatic controls are lost following viral pneumonia, CD8 TRM cells can mediate pulmonary pathology. We recently showed that the aging process can result in loss of homeostatic controls on CD8 TRM cells in the respiratory tract. This may be germane to treatment modalities in both influenza and coronavirus disease 2019 (COVID-19) patients, particularly, the portion that present with symptoms linked to long-lasting lung dysfunction. Here, we review the developmental cues and functionalities of CD8 TRM cells in viral pneumonia models with a particular focus on their capacity to mediate heterogeneous responses of immunity and pathology depending on immune status.


Assuntos
Linfócitos T CD8-Positivos/imunologia , /virologia , Memória Imunológica , Pulmão/imunologia , Pulmão/virologia , /imunologia , Fatores Etários , Animais , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , /patologia , Resistência à Doença/imunologia , Homeostase , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunofenotipagem , Pulmão/metabolismo , Pulmão/patologia , Contagem de Linfócitos , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
2.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803282

RESUMO

Systemic sclerosis (SSc) is an autoimmune disorder characterized by fibrosis of the skin and internal organs. Despite several studies on SSc treatments, effective treatments for SSc are still lacking. Since evidence suggests an association between intestinal microbiota and SSc, we focused on butyrate, which has beneficial effects in autoimmune diseases as a bacterial metabolite. Here, we investigated the therapeutic potential of sodium butyrate (SB) using a bleomycin-induced fibrosis mouse model of SSc and human dermal fibroblasts (HDFs). SB attenuated bleomycin-induced dermal and lung fibrosis in mice. SB influenced fecal microbiota composition (phyla Actinobacteria and Bacteroidetes, genera Bifidobacterium and Ruminococcus_g2). SB controlled macrophage differentiation in mesenteric lymph nodes, spleen, and bronchoalveolar lavage cells of mice with bleomycin-induced skin fibrosis. Profibrotic and proinflammatory gene expression was suppressed by SB administration in skin. Furthermore, SB inhibited transforming growth factor ß1-responsive proinflammatory expression with increased acetylation of histone 3 in HDFs. Subcutaneous SB application had antifibrogenic effects on the skin. Butyrate ameliorated skin and lung fibrosis by improving anti-inflammatory activity in a mouse model of SSc. Butyrate may exhibit indirect and direct anti-fibrogenic action on fibroblasts by regulating macrophage differentiation and inhibition of histone deacetylase 3. These findings suggest butyrate as an SSc treatment.


Assuntos
Bleomicina/efeitos adversos , Butiratos/farmacologia , Disbiose , Fibrose Pulmonar , Dermatopatias , Animais , Bleomicina/farmacologia , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Masculino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Dermatopatias/induzido quimicamente , Dermatopatias/tratamento farmacológico , Dermatopatias/microbiologia
3.
Respir Res ; 22(1): 99, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823870

RESUMO

BACKGROUND: COVID-19 pneumonia has been associated with severe acute hypoxia, sepsis-like states, thrombosis and chronic sequelae including persisting hypoxia and fibrosis. The molecular hypoxia response pathway has been associated with such pathologies and our recent observations on anti-hypoxic and anti-inflammatory effects of whole aqueous extract of Adhatoda Vasica (AV) prompted us to explore its effects on relevant preclinical mouse models. METHODS: In this study, we tested the effect of whole aqueous extract of AV, in murine models of bleomycin induced pulmonary fibrosis, Cecum Ligation and Puncture (CLP) induced sepsis, and siRNA induced hypoxia-thrombosis phenotype. The effect on lung of AV treated naïve mice was also studied at transcriptome level. We also determined if the extract may have any effect on SARS-CoV2 replication. RESULTS: Oral administration AV extract attenuates increased airway inflammation, levels of transforming growth factor-ß1 (TGF-ß1), IL-6, HIF-1α and improves the overall survival rates of mice in the models of pulmonary fibrosis and sepsis and rescues the siRNA induced inflammation and associated blood coagulation phenotypes in mice. We observed downregulation of hypoxia, inflammation, TGF-ß1, and angiogenesis genes and upregulation of adaptive immunity-related genes in the lung transcriptome. AV treatment also reduced the viral load in Vero cells infected with SARS-CoV2. CONCLUSION: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features and highlights the repurposing potential of AV in COVID-19-like conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Reposicionamento de Medicamentos , Hipóxia/tratamento farmacológico , Adhatoda , Pulmão/efeitos dos fármacos , Extratos Vegetais/farmacologia , Pneumonia/prevenção & controle , Fibrose Pulmonar/tratamento farmacológico , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Bleomicina , /virologia , Ceco/microbiologia , Ceco/cirurgia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Hipóxia/genética , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Mediadores da Inflamação/metabolismo , Adhatoda/química , Ligadura , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Pneumonia/genética , Pneumonia/metabolismo , Pneumonia/microbiologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Sepse/genética , Sepse/metabolismo , Sepse/microbiologia , Transcriptoma
5.
Methods Mol Biol ; 2269: 83-92, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33687673

RESUMO

A co-culture model of mesenchymal stem cells (MSCs) and fibroblasts is an efficient and rapid method to evaluate the anti-fibrotic effects of MSCs-based cell therapy. Transforming growth factor (TGF)-ß1 plays a key role in promotion of fibroblast activation and differentiation which can induce collagen deposition, increase ECM production in lung tissue, eventually resulted in pulmonary fibrosis. Here, we use this co-culture system and examine the ECM production in activated fibroblasts by western blot and quantitative real-time analysis to understand the therapeutic effects of MSCs.


Assuntos
Fibroblastos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/efeitos adversos , Animais , Linhagem Celular , Técnicas de Cocultura , Fibroblastos/patologia , Células-Tronco Mesenquimais/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta1/farmacologia
6.
Toxicol Appl Pharmacol ; 418: 115501, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33771551

RESUMO

With the rapid increase in application of disinfectants worldwide as a method to block the spread of coronavirus, many new products are being introduced into the market without thorough verification of their impacts on human health and the environment. In the present study, we aimed to propose a screening marker for materials that can induce fibrotic lung disease using disinfectants, which had been demonstrated as causative materials of chronic inflammation and interstitial fibrosis. We first calculated the corresponding LC50 level based on results from cell viability test and exposed the LC50 level of disinfectants to human bronchial epithelial cells for 24 h. Formation of lamellar body-like structures, cleavage of the nuclear matrix, structural damage of mitochondria were found in the cytosol of the treated cells. We also dosed disinfectants by pharyngeal aspiration to mice to determine the LD0 level. The mice were sacrificed on Day 14 after a single dosing, and lamellar body-like structures were observed in the lung tissue of mice. Herein, we hypothesize that DNA damage and metabolic disturbance may play central roles in disinfectant-induced adverse health effects. Additionally, we propose that formation of lamellar bodies can be a screening marker for interstitial fibrosis.


Assuntos
Desinfetantes/toxicidade , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Líquido Intracelular/efeitos dos fármacos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/patologia , Animais , Biomarcadores/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Epiteliais/metabolismo , Feminino , Humanos , Líquido Intracelular/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
7.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530568

RESUMO

Airway epithelial cell death contributes to the pathogenesis of lung fibrosis. Polyhexamethylene guanidine phosphate (PHMG-p), commonly used as a disinfectant, has been shown to be strongly associated with lung fibrosis in epidemiological and toxicological studies. However, the molecular mechanism underlying PHMG-p-induced epithelial cell death is currently unclear. We synthesized a PHMG-p-fluorescein isothiocyanate (FITC) conjugate and assessed its uptake into lung epithelial A549 cells. To examine intracellular localization, the cells were treated with PHMG-p-FITC; then, the cytoplasmic organelles were counterstained and observed with confocal microscopy. Additionally, the organelle-specific cell death pathway was investigated in cells treated with PHMG-p. PHMG-p-FITC co-localized with the endoplasmic reticulum (ER), and PHMG-p induced ER stress in A549 cells and mice. The ER stress inhibitor tauroursodeoxycholic acid (TUDCA) was used as a pre-treatment to verify the role of ER stress in PHMG-p-induced cytotoxicity. The cells treated with PHMG-p showed apoptosis, which was inhibited by TUDCA. Our results indicate that PHMG-p is rapidly located in the ER and causes ER-stress-mediated apoptosis, which is an initial step in PHMG-p-induced lung fibrosis.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Guanidinas/farmacologia , Células A549 , Animais , Células Cultivadas , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Citometria de Fluxo , Humanos , Camundongos , Fosforilação , Transporte Proteico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Transdução de Sinais
8.
DNA Cell Biol ; 40(4): 589-594, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33600261

RESUMO

Silicosis is an irreversible occupational pulmonary disease that is characterized as progressed pulmonary fibrosis. In this study, we investigated the changes of UFSP2 and the related UFMylation in silica-induced pulmonary injury mice models. The experimental silicosis models were prepared by intratracheal injection of silica particles, and the lung samples were harvested at the first or the seventh day after treatment. We found that the UFSP2 expression in the 1-day models was comparable, whereas it was upregulated in the 7-day models. Consistently, the UFMylation in the lung tissues of the 7-day models was activated. In addition, we observed the CADM2, an adhesion molecule, was reported to associate with epithelial-mesenchymal transition, was upregulated in the lungs of 7-day models. In contrast, it remained comparable in the 1-day models. Our data indicated that the UFSP2/UFMylation pathway and the CADM2 might be involved in the silica-induced pulmonary injury.


Assuntos
Cisteína Endopeptidases/metabolismo , Proteínas/metabolismo , Silicose/metabolismo , Animais , China , Cisteína Endopeptidases/fisiologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal , Pulmão/metabolismo , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Dióxido de Silício/efeitos adversos , Silicose/fisiopatologia
9.
Respir Res ; 22(1): 38, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546680

RESUMO

Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.


Assuntos
/metabolismo , Matriz Extracelular/metabolismo , Fibrose Pulmonar/metabolismo , Cicatrização/fisiologia , Animais , Biomarcadores/metabolismo , Humanos , Pulmão/metabolismo , Fibrose Pulmonar/diagnóstico
10.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495816

RESUMO

Pulmonary fibrosis is an excessive repair response to tissue damage, triggering hyperplasia of fibrotic connective tissues; however, there is no effective treatment in a clinical setting. The purpose of the present study was to investigate the roles of long non­coding RNA nuclear enriched abundant transcript 1 (NEAT1) and microRNA­455­3p (miR­455­3p) were investigated in pulmonary fibrosis. In this study, the mRNA expression levels of NEAT1, miR­455­3p and SMAD3 in the HPAEpiC alveolar and BEAS­2B bronchial epithelial cell lines were determined using reverse transcription­quantitative PCR, while the markers of epithelial­mesenchymal transformation (EMT) and collagen production were determined using western blot analysis. A wound healing assay was performed to evaluate the migratory ability of the HPAEpiC and BEAS­2B cell lines. The interactions between NEAT1 and miR­455­3p or SMAD3 and miR­455­3p were validated using a luciferase reporter gene assay. The results showed that the mRNA expression levels of NEAT1 and SMAD3 were upregulated in the TGF­ß1­treated HPAEpiC and BEAS­2B cell lines, while the mRNA expression level of miR­455­3p was significantly decreased. In addition, silencing NEAT1 effectively alleviated the migratory ability, EMT and collagen generation of the epithelial cells. Following these experiments, NEAT1 was identified as a sponge for miR­455­3p, and SMAD3 was a target gene of miR­455­3p. NEAT1 downregulation or miR­455­3p mimic inhibited the migratory ability, EMT and collagen production of the epithelial cells; however, the effects were reversed by the overexpression of SMAD3. Furthermore, NEAT1 knockdown reduced the expression level of SMAD3 by increasing the expression level of miR­455­3p to further inhibit the migratory ability, EMT and collagen production of epithelial cells.


Assuntos
Células Epiteliais/metabolismo , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Linhagem Celular , Células Epiteliais/patologia , Humanos , MicroRNAs/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , RNA Longo não Codificante/genética , Proteína Smad3/genética
11.
Life Sci ; 269: 119085, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33482190

RESUMO

Pulmonary fibrosis (PF), which is characterized by excessive matrix formation, may ultimately lead to irreversible lung damage and thus death. Fibroblast activation has been regarded as a central event during PF pathogenesis. In our previous study, we confirmed that the miR-627/high-mobility group box protein 1 (HMGB1)/Nuclear factor kappa beta (NF-κB) axis modulates transforming growth factor beta 1 (TGFß1)-induced pulmonary fibrosis. In the present study, we investigated the upstream factors leading to miR-627 dysregulation in the process of pulmonary fibroblast activation and PF. The lncRNA MIR155 host gene (MIR155HG) was found to be abnormally upregulated in pulmonary fibrosis tissues and TGFß1-stimulated normal human primary lung fibroblasts (NHLFs). By directly binding to miR-627, MIR155HG inhibited miR-627 expression. MIR155HG overexpression enhanced TGFß1-induced increases in HMGB1 protein expression and p65 phosphorylation, NHLF proliferation, and extracellular matrix (ECM) deposition. In contrast, miR-627 overexpression attenuated the TGFß1-induced changes in NHLFs and significantly reversed the effects of MIR155HG overexpression. Under TGFß1 stimulation, miR-627 inhibition promoted, whereas JSH-23 treatment inhibited NF-κB activation; in NHLFs, NF-κB overexpression upregulated, whereas JSH-23 treatment downregulated MIR155HG expression. In tissue samples, HMGB1 protein levels and p65 phosphorylation were increased; MIR155HG was negatively correlated with miR-627 and positively correlated with HMGB1. In conclusion, we validated that the MIR155HG/miR-627/HMGB1/NF-κB axis formed a regulatory loop that modulates TGFß1-induced NHLF activation. Considering the critical role of NHLF activation in PF pathogenesis, the NF-κB/MIR155HG/miR-627/HMGB1 regulatory loop could exert a vital effect on PF pathogenesis. Further in vivo and clinical investigations are required to confirm this model.


Assuntos
Matriz Extracelular/metabolismo , Fibroblastos/citologia , Proteína HMGB1/metabolismo , MicroRNAs/genética , NF-kappa B/metabolismo , Fibrose Pulmonar/patologia , RNA Longo não Codificante/genética , Estudos de Casos e Controles , Proliferação de Células , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Proteína HMGB1/genética , Humanos , Pulmão/citologia , Pulmão/metabolismo , NF-kappa B/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
12.
Ecotoxicol Environ Saf ; 205: 111327, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961493

RESUMO

Exposure to PM2.5 can cause serious harm to the respiratory system. Until now, although many toxicological studies have shown that pulmonary fibrosis can be caused by long-term PM2.5 exposure, there is no evidence that Endothelial-Mesenchymal Transition (EndMT) can trigger the process of pulmonary fibrosis after exposure. LncRNAs are a class of non-coding RNAs detected in mammalian cells. Nevertheless, researchers have not found whether lncRNAs participate in PM2.5 induced EndMT during pathophysiological duration. The Balb/c mouse model was exposed to PM2.5 for 4 months by dynamic intoxication. The levels of specific endothelial and mesenchymal markers were evaluated by molecular biology experiments to elucidate the mechanisms of EndMT induced by PM2.5 in lung tissues. LncRNA microarray analysis of the established mouse model of PM2.5 exposure was performed. Based on a bioinformatics analysis and RT-qPCR analysis, lncRNA Gm16410 attracted our attention. The change of lncRNA Gm16410 in mouse pulmonary vascular endothelial cells (MHCs) exposed to PM2.5 was verified, and the mechanism of lncRNA Gm16410 in EndMT was discussed. The changes of cell function were evaluated by cell migration and proliferation experiments. The molecular biology experiments proved that PM2.5 induced EndMT by activating the TGF-ß1/Smad3/p-Smad3 pathway in vitro. The relationship of EndMT and lncRNA Gm16410 was verified in mouse lung tissues and MHC cells by PM2.5 exposure. The involvement of lncRNA Gm16410 in PM2.5-induced EndMT highlights the potential of lncRNA to promote pulmonary fibrosis under environmental pollution.


Assuntos
Material Particulado/toxicidade , RNA Longo não Codificante/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Pulmão/metabolismo , Camundongos , Material Particulado/metabolismo , Fibrose Pulmonar/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3 , Fator de Crescimento Transformador beta1/metabolismo
13.
Life Sci ; 260: 118399, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32918977

RESUMO

Pulmonary fibrosis is the end stage of many interstitial lung diseases, characterized by the deposition of excess extracellular matrix (ECM), destruction of normal alveolar structure, and resulting in the obstruction of gas exchange and respiratory failure. The idiopathic pulmonary fibrosis (IPF) is the most common form of pulmonary fibrosis with little effective therapies. 5-Methoxytryptophan (5-MTP) is a newly found tryptophan metabolite. Previous studies suggested that 5-MTP has the effects of anti-inflammatory, anti-tumorigenesis, vascular protection and anti-fibrosis in renal disease. Whether 5-MTP has therapeutic effect on pulmonary fibrosis is not clear. In our study, we used TGF-ß1 to stimulate human lung fibroblasts (HLFs) and bleomycin (BLM) induced pulmonary fibrosis model to investigate the effect of 5-MTP on pulmonary fibrosis. Our study demonstrated that 5-MTP could improve the lung function and attenuate the destruction of alveolar structure in BLM-induced pulmonary fibrosis mice. Furthermore, 5-MTP significantly decreased accumulation of myofibroblasts and the deposition of ECM by inhibiting the differentiation of fibroblasts to myofibroblasts and suppressing the protein expression of the ECM both in vivo and in vitro. Our results also revealed 5-MTP could inhibit the proliferation and migration of the fibroblasts in vitro, which played an important role in the progressive pulmonary fibrosis. To further investigate the mechanism of the anti-fibrosis of 5-MTP, several canonical and noncanonical signaling pathways were examined. Our results revealed that 5-MTP could inhibit the pulmonary fibrosis through downregulating the phosphorylation of TGF-ß/SMAD3, PI3K/AKT signaling pathways. Together, our study indicated that 5-MTP promises to be therapeutic agent of pulmonary fibrosis.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Triptofano/análogos & derivados , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Diferenciação Celular , Matriz Extracelular , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Proteína Smad3/genética , Fator de Crescimento Transformador beta/genética , Triptofano/farmacologia
14.
Life Sci ; 259: 118286, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32810508

RESUMO

AIMS: To investigate the role of CX3CR1 in hyperoxic lung injury induced pulmonary fibrosis. MATERIALS AND METHODS: Hyperoxic lung injured mice were used as the disease model. Pulmonary fibrosis was determined by H&E and Masson's staining. Autophagy was investigated by western blot, immunofluorescence staining, and transmission electron microscopy. KEY FINDINGS: We observed that increased CX3CR1 expression corresponded with increased pulmonary fibrosis. Additionally, silencing of CX3CR1 significantly alleviated the fibrosis when compared to the control. We observed that exposure of mouse to hyperoxic environment increased macrophage levels along with an increased CD11b expression in the lung tissues. Subsequently, we also observed an increased expression of LC3-II and decreased p62 expression in hyperoxic mice models, suggesting the potential role of hyperoxia induced autophagy. CD11b and LC3/CX3CR1 were expressed and co-localized in a manner indicating CX3CR1 indeed does regulate macrophage autophagy in the hyperoxic lung injury model. We observed a decrease in hyperoxia-associated fibrosis, along with a decrease in autophagy when we used 3-MA (autophagy inhibitor) in our hyperoxic lung injury model. To elucidate the pathway through which CX3CR1 regulated autophagy, we further analyzed the Akt1 pathway. Our experimental results indicated that the Akt1 inhibitor (A-674563) did significantly decrease macrophage autophagy and fibrosis in hyperoxic mice models. SIGNIFICANCE: Thus, our data indicates a novel role of CX3CR1 in regulation of macrophage autophagy and promotion of pulmonary fibrosis in hyperoxic lung injured mice.


Assuntos
Receptor 1 de Quimiocina CX3C/metabolismo , Hiperóxia/metabolismo , Lesão Pulmonar/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Autofagia/fisiologia , Western Blotting , Receptor 1 de Quimiocina CX3C/antagonistas & inibidores , Modelos Animais de Doenças , Hiperóxia/patologia , Pulmão/metabolismo , Lesão Pulmonar/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/patologia
15.
Life Sci ; 258: 118201, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781070

RESUMO

Fibrotic lung diseases qualify among the most dreaded irreversible interstitial pulmonary complications with progressive yet largely unpredictable clinical course. Idiopathic pulmonary fibrosis (IPF) is the most challenging prototype characterized by unknown and complex molecular etiology, severe dearth of non-invasive therapeutic options and average lifespan of 2-5 years in patients post diagnosis. Lung fibrosis (LF) is a leading cause of death in the industrialized world with the propensity to contract, significantly increasing with age. Approximately 45% deaths in US are attributed to fibrotic diseases while around 7% respiratory disease-associated deaths, annually in UK, are actually attributed to IPF. Recent developments in the field of LF have unambiguously pointed towards the pivotal role of Sirtuins (SIRTs) in regulating disease progression, thereby qualifying as potential anti-fibrotic drug targets. These NAD+-dependent lysine deacetylases, deacylases and ADP-ribosyltransferases are evolutionarily conserved proteins, regulated by diverse metabolic/environmental factors and implicated in age-related degenerative and inflammatory disorders. While SIRT1, SIRT6 and SIRT7 are predominantly nuclear, SIRT3, SIRT4, SIRT5 are mainly mitochondrial and SIRT2 is majorly cytosolic with occasional nuclear translocation. SIRT1, SIRT3, SIRT6 and SIRT7 are documented as cytoprotective sirtuins implicated in cardiovascular, pulmonary and metabolic diseases including fibrosis; however functional roles of remaining sirtuins in pulmonary pathologies are yet elusive. Here, we provide a comprehensive recent update on the regulatory role of sirtuins on LF along with discussion on potential therapeutic modulation of endogenous Sirtuin expression through synthetic/plant-derived compounds which can help synthetic chemists and ethnopharmacologists to design new-generation cheap, non-toxic Sirtuin-based drugs against LF.


Assuntos
Pulmão/metabolismo , Pulmão/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Sirtuínas/metabolismo , Animais , Humanos , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais
16.
Toxicol Lett ; 333: 170-183, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32795487

RESUMO

Paraquat (PQ) poisoning-induced pulmonary fibrosis always results in fatal harm to patients. Our study aimed to investigate the functions of the Wnt/ß-catenin pathway in PQ-induced pulmonary fibrosis. By comparing the proteomic profiles of rat lung tissues using protein array in the absence or presence of PQ, the Wnt/ß-catenin signaling, as a fibrosis-related pathway, was discovered to be profoundly activated by PQ. The protein levels of Wnt/ß-catenin signaling components including MMP-2, ß-catenin, Wnt3a, Wnt10b, Cyclin D1, and WISP1 were increased in PQ-treated rat lung tissues. Surprisingly, PQ was found to be able to promote lung epithelial cells and fibroblasts differentiating into myofibroblasts by activating Wnt/ß-catenin signaling pathway. Dickkopf-1 (DKK1), an antagonist of Wnt/ß-catenin signaling pathway, could inhibit the myofibroblast differentiation and attenuate PQ-induced pulmonary fibrogenesis in vitro and in vivo. The expression levels of fibroblasts markers Vimentin, α-smooth muscle actin (α-SMA) and Collagen I was detected and found to be increased when PQ treated and restored with additional DKK1 treatment. In summary, these assays indicated that Wnt/ß-catenin signaling pathway played a regulatory role in the differentiation of lung epithelial cells and fibroblasts, and the pathogenesis of pulmonary fibrosis related to PQ. Inhibition of the Wnt/ß-catenin signaling pathway may be investigated further as a potential fibrosis suppressor for pulmonary fibrosis therapy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Herbicidas/toxicidade , Miofibroblastos/efeitos dos fármacos , Paraquat/toxicidade , Fibrose Pulmonar/induzido quimicamente , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley
17.
Nat Commun ; 11(1): 4254, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848143

RESUMO

Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFß1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFß1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF.


Assuntos
Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Tiorredoxinas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Bleomicina/toxicidade , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Deleção de Genes , Humanos , Fibrose Pulmonar Idiopática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isomerases de Dissulfetos de Proteínas/genética , Dobramento de Proteína , Estabilidade Proteica , Fibrose Pulmonar/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Transdução de Sinais , Tiorredoxinas/antagonistas & inibidores , Tiorredoxinas/genética , Regulação para Cima
18.
Int J Mol Sci ; 21(15)2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32727145

RESUMO

In March 2020, the World Health Organization declared the severe acute respiratory syndrome corona virus 2 (SARS-CoV2) infection to be a pandemic disease. SARS-CoV2 was first identified in China and, despite the restrictive measures adopted, the epidemic has spread globally, becoming a pandemic in a very short time. Though there is growing knowledge of the SARS-CoV2 infection and its clinical manifestations, an effective cure to limit its acute symptoms and its severe complications has not yet been found. Given the worldwide health and economic emergency issues accompanying this pandemic, there is an absolute urgency to identify effective treatments and reduce the post infection outcomes. In this context, phosphodiesterases (PDEs), evolutionarily conserved cyclic nucleotide (cAMP/cGMP) hydrolyzing enzymes, could emerge as new potential targets. Given their extended distribution and modulating role in nearly all organs and cellular environments, a large number of drugs (PDE inhibitors) have been developed to control the specific functions of each PDE family. These PDE inhibitors have already been used in the treatment of pathologies that show clinical signs and symptoms completely or partially overlapping with post-COVID-19 conditions (e.g., thrombosis, inflammation, fibrosis), while new PDE-selective or pan-selective inhibitors are currently under study. This review discusses the state of the art of the different pathologies currently treated with phosphodiesterase inhibitors, highlighting the numerous similarities with the disorders linked to SARS-CoV2 infection, to support the hypothesis that PDE inhibitors, alone or in combination with other drugs, could be beneficial for the treatment of COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Fibrose Pulmonar/prevenção & controle , Betacoronavirus/efeitos dos fármacos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Progressão da Doença , Humanos , Pandemias , Inibidores de Fosfodiesterase/farmacologia , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento
19.
Mol Immunol ; 125: 15-22, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32619930

RESUMO

PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin (BLM)-induced pulmonary fibrosis. In a BLM-induced pulmonary fibrosis model, PIM1 was persistently upregulated in fibrotic lung tissues. Furthermore, PIM1 inhibition by the PIM1-specific inhibitor SMI-4a showed protective effects against BLM-induced mortality. Furthermore, SMI-4a suppressed hydroxyproline deposition and reversed epithelial-mesenchymal transition (EMT) formation, which was characterized by E-cadherin and α-SMA expression in vivo. More importantly, the ZEB1/E-cadherin pathway was found to be closely associated with BLM-induced pulmonary fibrosis. After the in vitro treatment of A549 cells, PIM1 regulated E-cadherin expression by dependently modulating the activity of the transcription factor ZEB1. These findings were verified in vivo after SMI-4a administration. Finally, an shPIM1-expressing adeno-associated virus was delivered via intratracheal injection to induce a long-term PIM1 deficiency in the alveolar epithelium. AAV-mediated PIM1 knockdown in the lung tissues alleviated BLM-induced pulmonary fibrosis, as indicated by collagen accumulation reduction, pulmonary histopathological mitigation and EMT reversion. These findings enhance our understanding of the roles of PIM1 in BLM-induced pulmonary fibrosis and suggest PIM1 inhibition as a potential therapeutic strategy in chronic pulmonary injuries.


Assuntos
Células Epiteliais Alveolares/metabolismo , Caderinas/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fibrose Pulmonar/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Células A549 , Células Epiteliais Alveolares/patologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia
20.
Nat Commun ; 11(1): 3559, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678092

RESUMO

The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell-cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.


Assuntos
Células Epiteliais Alveolares/metabolismo , Queratina-8/metabolismo , Alvéolos Pulmonares/fisiologia , Fibrose Pulmonar/patologia , Regeneração , Células-Tronco/metabolismo , Células Epiteliais Alveolares/citologia , Animais , Comunicação Celular , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Queratina-8/genética , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/citologia , Fibrose Pulmonar/metabolismo , Análise de Célula Única , Células-Tronco/citologia
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