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1.
Chem Biol Interact ; 319: 109024, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097614

RESUMO

Silicosis is an occupational pulmonary fibrosis that is caused by inhalation of silica (SiO2), and there are no effective drugs to treat this disease. Tanshinone IIA (Tan IIA), a natural product, has been reported to possess antioxidant and anti-fibrotic properties in various diseases. The purpose of the current study was to examine Tan IIA's protective effects against silica-induced pulmonary fibrosis and to explore the underlying mechanisms. We found that in vivo treatment with Tan IIA significantly relieved silica-induced lung fibrosis in a silicosis rat model by histological and immunohistochemical analyses. Further, in vitro mechanistic investigations, mainly using western blot and immunofluorescence analyses, revealed that Tan IIA administration markedly inhibited the silica-induced epithelial-mesenchymal transition (EMT) and transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway and also reduced silica-induced oxidative stress and activated the nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway in A549 and human bronchial epithelial (HBE) cells. Furthermore, through transfection with siRNA, we demonstrate that Nrf2 activation partially mediates the suppression effects of Tan IIA on EMT and TGF-ß1/Smad signaling pathway activation induced by silica exposure, thus mediating the anti-fibrotic effects of Tan IIA against silica-induced pulmonary fibrosis. In our study, Tan IIA has been identified as a possible anti-oxidative and anti-fibrotic drug for silicosis.


Assuntos
/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Células A549 , Animais , Antioxidantes/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Dióxido de Silício/farmacologia
2.
Cell Physiol Biochem ; 54(2): 195-210, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32083406

RESUMO

BACKGROUND/AIMS: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-ß1 (TGF-ß1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-ß1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-ß1 signaling and the pathogenesis of pulmonary fibrosis remain unknown. METHODS: We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies. RESULTS: Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-ß1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-ß1-induced Smad3 nuclear translocation and smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis. CONCLUSION: These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis.


Assuntos
Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteína Smad3/metabolismo , Animais , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Isoquinolinas/farmacologia , Cetonas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Piridinas/farmacologia , Pirróis/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/genética , Ativação Transcricional/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo
3.
Life Sci ; 241: 117139, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31809714

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious lung problem with advancing and diffusive pulmonary fibrosis as the pathologic basis, and with oxidative stress and inflammation as the key pathogenesis. Glycyl-L-histidyl-l-lysine (GHK) is a tripeptide participating into wound healing and regeneration. GHK-Cu complexes improve GHK bioavailability. Thus, the current study aimed to explore the therapeutic role of GHK-Cu on bleomycin (BLM)-induced pulmonary fibrosis in a mouse model. METHODS: BLM (3 mg/kg) was administered via tracheal instillation (TI) to induce a pulmonary fibrosis model in C57BL/6j mice 21 days after the challenge of BLM. GHK-Cu was injected intraperitoneally (i.p.) at different dosage of 0.2, 2 and 20 µg/g/day in 0.5 ml PBS on alternate day. The histological changes, inflammation response, the collagen deposition and epithelial-mesenchymal transition (EMT) was evaluated in the lung tissue. EMT was evaluated by ɑ-SMA and fibronectin expression in the lung tissue. NF-κB p65, Nrf2 and TGFß1/Smad2/3 signalling pathways were detected by immunoblotting analysis. RESULTS: GHK-Cu complex inhibited BLM-induced inflammatory and fibrotic pathological changes, alleviated the inflammatory response in the BALF by reducing the levels of the inflammatory cytokines, TNF-ɑ and IL-6 and the activity of MPO as well as reduced collagen deposition. In addition, the GHK-Cu treatment significantly reversed the MMP-9/TIMP-1 imbalance and partially prevented EMT via Nrf2, NF-κB and TGFß1 pathways, as well as Smad2/3 phosphorylation. CONCLUSIONS: GHK-Cu presented a protective effect in BLM-induced inflammation and oxidative stress by inhibiting EMT progression and suppressing TGFß1/Smad2/3 signalling in pulmonary fibrosis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Bleomicina/toxicidade , Cobre/administração & dosagem , Oligopeptídeos/administração & dosagem , Fibrose Pulmonar/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/toxicidade , Colágeno/metabolismo , Cobre/química , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligopeptídeos/química , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
4.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31600983

RESUMO

Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4's critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-ß expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-ß-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-ß-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-ß signaling.


Assuntos
Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Transdução de Sinais , Sindecana-4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Actinas/metabolismo , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Fibroblastos/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Knockout , Fibrose Pulmonar/patologia , Sindecana-4/genética
5.
Redox Biol ; 26: 101307, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31473487

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an increased mortality. Metabolic reprogramming has a critical role in multiple chronic diseases. Lung macrophages expressing the mitochondrial calcium uniporter (MCU) have a critical role in fibrotic repair, but the contribution of MCU in macrophage metabolism is not known. Here, we show that MCU regulates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and metabolic reprogramming to fatty acid oxidation (FAO) in macrophages. MCU regulated PGC-1α expression by increasing the phosphorylation of ATF-2 by the p38 MAPK in a redox-dependent manner. The expression and activation of PGC-1α via the p38 MAPK was regulated by MCU-mediated mitochondrial calcium uptake, which is linked to increased mitochondrial ROS (mtROS) production. Mice harboring a conditional expression of dominant-negative MCU in macrophages had a marked reduction in mtROS and FAO and were protected from pulmonary fibrosis. Moreover, IPF lung macrophages had evidence of increased MCU and mitochondrial calcium, increased phosphorylation of ATF2 and p38, as well as increased expression of PGC-1α. These observations suggest that macrophage MCU-mediated metabolic reprogramming contributes to fibrotic repair after lung injury.


Assuntos
Canais de Cálcio/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Adulto , Idoso , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-NH2/metabolismo , Consumo de Oxigênio , Fenótipo , Fibrose Pulmonar/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Immunity ; 51(3): 522-534.e7, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31471107

RESUMO

Although recent progress provides mechanistic insights into the pathogenesis of pulmonary fibrosis (PF), rare anti-PF therapeutics show definitive promise for treating this disease. Repeated lung epithelial injury results in injury-repairing response and inflammation, which drive the development of PF. Here, we report that chronic lung injury inactivated the ubiquitin-editing enzyme A20, causing progressive accumulation of the transcription factor C/EBPß in alveolar macrophages (AMs) from PF patients and mice, which upregulated a number of immunosuppressive and profibrotic factors promoting PF development. In response to chronic lung injury, elevated glycogen synthase kinase-3ß (GSK-3ß) interacted with and phosphorylated A20 to suppress C/EBPß degradation. Ectopic expression of A20 or pharmacological restoration of A20 activity by disturbing the A20-GSK-3ß interaction accelerated C/EBPß degradation and showed potent therapeutic efficacy against experimental PF. Our study indicates that a regulatory mechanism of the GSK-3ß-A20-C/EBPß axis in AMs may be a potential target for treating PF and fibroproliferative lung diseases.


Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Macrófagos/metabolismo , Fibrose Pulmonar/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina/metabolismo , Animais , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/fisiologia , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia , Regulação para Cima/fisiologia
7.
In Vivo ; 33(5): 1455-1461, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471392

RESUMO

BACKGROUND/AIM: Idiopathic pulmonary fibrosis (PF) is a fatal disorder of unknown aetiology with limited treatment options. Chitosan has antibacterial, antifungal, antioxidant, antitumour, and anti-inflammatory effects. This study aimed to investigate the effects of chitosan administration on bleomycin (BLM)-induced PF in rats. MATERIALS AND METHODS: A PF rat model was established by endotracheal instillation of 5 mg/kg BLM; then, chitosan was administered in drinking water for 3 weeks. Histology, cell counts, and cytokine responses in the bronchoalveolar lavage fluid (BALF) and weight measurements (body and lung) were analyzed to assess its therapeutic effects. RESULTS: Chitosan administration tended to reduce transforming growth factor (TGF)-ß1 and interferon (IFN)-γ levels in BALF, and histopathological examination confirmed that chitosan attenuated the degree of inflammation and fibrosis in the lung. CONCLUSION: This study revealed that oral chitosan exhibits potential antifibrotic effects, as measured by decreased proinflammatory cytokine levels and histological evaluation, in a BLM-induced PF rat model.


Assuntos
Bleomicina/efeitos adversos , Quitosana/administração & dosagem , Substâncias Protetoras/administração & dosagem , Fibrose Pulmonar/etiologia , Administração Oral , Animais , Biópsia , Modelos Animais de Doenças , Progressão da Doença , Imuno-Histoquímica , Masculino , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos , Resultado do Tratamento
8.
Biomed Pharmacother ; 119: 109387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487583

RESUMO

PURPOSE: To observe the effect of astragaloside ASV (ASV) on silicosis fibroblasts, and further investigate its regulatory mechanism on TGF-ß1/Smad3 signaling pathway. METHODS: Silica-induced rats model was established in this study. RT-qPCR was performed to detect α-SMA, Collagen I, Collagen III, Smad2, Smad3 and Smad7 expression. Immunofluorescence was conducted to detect α-SMA, Collagen I, Collagen III and p-Smad3 protein and the nucleoplasmic distribution of p-Smad3.Western-blotting was performed to detect the protein of Smad2, p-Smad2, Smad3, p-Smad3 and Smad7. RESULTS: 20 µg/mL ASV could effectively reduce the expression of α-SMA, Collagen I, Collagen III. TGF-ß1 stimulated the proliferation of fibroblasts, promoted phosphorylation of Smad2 and Smad3, and down-regulated Smad7 expression. Among them, continuous phosphorylation of Smad3 is a major factor in causing fibrosis. Besides, ASV can inhibit silica-induced lung fibroblast fibrosis through TGF-ß1/Smad3 signaling pathway, thereby inhibiting the formation of silicosis. CONCLUSION: ASV could inhibit the expression of collagen in fibroblasts and the transformation to myofibroblasts, and has an anti-silicosis fibrosis effect, which may be related to the continuous phosphorylation of Smad3 in the TGF-ß1/Smad signaling pathway.


Assuntos
Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Saponinas/uso terapêutico , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Triterpenos/uso terapêutico , Actinas/genética , Actinas/metabolismo , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Regulação para Baixo/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Pulmão/patologia , Fosforilação/efeitos dos fármacos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Ratos Wistar , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício , Silicose/tratamento farmacológico , Silicose/metabolismo , Silicose/patologia , Proteína Smad2/metabolismo , Triterpenos/farmacologia
9.
Int J Mol Sci ; 20(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398940

RESUMO

Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field.


Assuntos
Células-Tronco Mesenquimais/metabolismo , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Lesões por Radiação/metabolismo , Animais , Biomarcadores , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Transplante de Células-Tronco Mesenquimais , Fibrose Pulmonar/patologia , Fibrose Pulmonar/terapia , Lesões por Radiação/patologia , Lesões por Radiação/terapia , Radioterapia/efeitos adversos , Regeneração
10.
J Agric Food Chem ; 67(35): 9789-9795, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31373816

RESUMO

Pulmonary fibrosis is a chronic lung disease characterized by abnormal accumulation of the extracellular matrix (ECM). Chronic damage of the alveolar epithelium leads to a process called "epithelial-mesenchymal transition" (EMT) and increases synthesis and deposition of ECM proteins. Therefore, inhibition of EMT might be a promising therapeutic approach for the treatment of pulmonary fibrosis. ß-Sitosterol is one of the most abundant phytosterols in the plant kingdom and the major constituent in corn silk, which is derived from the stigma and style of maize (Zea mays). In this study, we elucidated that ß-sitosterol inhibited transforming growth factor-ß1 (TGF-ß1)-induced EMT and consequently had an antifibrotic effect. ß-Sitosterol (1-10 µg/mL) significantly downregulated the TGF-ß1-induced fibrotic proteins, such as collagen, fibronectin, and α-smooth muscle actin in human alveolar epithelial cells (p < 0.01). After 24 h, relative wound density (RWD) was increased in TGF-ß1 treated group (82.16 ± 5.70) compare to the control group (64.63 ± 2.21), but RWD was decreased in ß-sitosterol cotreated group (10 µg/mL: 71.54 ± 7.39; 20 µg/mL: 65.69 ± 6.42). In addition, the changes of the TGF-ß1-induced morphological shape and protein expression of EMT markers, N-cadherin, vimentin, and E-cadherin, were significantly blocked by ß-sitosterol treatment (p < 0.01). The effects of ß-sitosterol on EMT were found to be associated with the TGF-ß1/Snail pathway, which is regulated by Smad and non-Smad signaling pathways. Taken together, these findings suggest that ß-sitosterol can be used to attenuate pulmonary fibrosis through suppression of EMT by inhibiting the TGF-ß1/Snail pathway.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Extratos Vegetais/farmacologia , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/fisiopatologia , Sitosteroides/farmacologia , Zea mays/química , Actinas/genética , Actinas/metabolismo , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Extratos Vegetais/química , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/fisiopatologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
11.
Biomed Pharmacother ; 118: 109293, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31401393

RESUMO

Pulmonary fibrosis (PF) is a crippling disease characterized by progressive dyspnea and associated with a high mortality rate, but its origin is unknown and there is no effective treatment. Yifei Sanjie formula (YFSJF) is a Chinese medicine that is widely used for treatment of respiratory systems disease. However, the molecular basis for the function of YFSJF has not been determined. Here we investigate the contribution of YFSJF in BLM-induced PF mice. Administration with YFSJF significantly alleviated the degree of BLM-induced collagen I and III deposition and the inflammatory injuring in the lungs and suppressed hydroxyproline release in PF animals. The active components of YFSJF are comprised with flavonoid, amino acids, saponins, oligosaccharide, organic acid, vitamin, esters, purine nucleosides. Additionally, there was a significant increase in autophagosomes, after treatment with YFSJF in PF animals. Interestingly, autophagy dysfunction by the blocker chloroquine (CQ) resulted in collagen deposition and inducing the expression of fibrosis-related genes. In addition, YFSJF-induced autophagy is mediated by the PI3K-AKT-mTOR pathway, and knockdown of PI3K by siRNA up-regulated the expression of autophagy-related genes and down-regulated the expression of collagen in human lung fibroblasts (HLF). Our findings provide a detailed understanding that YFSJF-antifibrotic effects are mainly mediated by triggering autophagy, and suppressing phosphorylation of the PI3K-AKT-mTOR pathway is required for YFSJF-curative effect.


Assuntos
Autofagia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas , Humanos , Inflamação/complicações , Inflamação/patologia , Pulmão/patologia , Masculino , Fosforilação/efeitos dos fármacos , Fibrose Pulmonar/complicações , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Med Sci Monit ; 25: 6153-6164, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419218

RESUMO

BACKGROUND The clinical association between gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) has been known for many years, but it is still unclear. The present study investigated the association between experimentally simulated aspiration and pulmonary fibrosis. MATERIAL AND METHODS A total of 120 male Sprague-Dawley rats were randomly divided into a negative control group, a bleomycin group, and 3 simulated aspiration groups. The bleomycin group was administered a one-time intratracheal injection of bleomycin, whereas the 3 simulated aspiration groups were treated either with an intratracheal instillation of gastric fluid combined with pepsin, with pepsin alone, or with hydrochloric acid, all twice a week, and the negative control group was administered normal saline twice a week. Lung tissues were collected to evaluate pathological changes and the mRNA expression levels of connective tissue growth factor (CTGF), type I collagen, and transforming growth factor. RESULTS The results demonstrated that the degree of fibrosis in the early stage was low in each of the 3 simulated aspiration groups, but gradually increased over time. The expression levels of the downstream factor of fibrosis, CTGF, and type I collagen also reflected this trend. CONCLUSIONS The study demonstrates that aspiration of gastric contents can cause pulmonary fibrosis, and mixed aspiration of pepsin and gastric fluid can accelerate this process. This study provides strong evidence in support of a potential association between human GERD and IPF.


Assuntos
Ácido Gástrico/metabolismo , Pepsina A/metabolismo , Fibrose Pulmonar/metabolismo , Administração por Inalação , Animais , Bleomicina/farmacologia , Proteína Rica em Cisteína 61/genética , Ácido Gástrico/fisiologia , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/fisiopatologia , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Masculino , Pepsina A/fisiologia , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Fatores de Crescimento Transformadores/genética
13.
Respir Res ; 20(1): 163, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331325

RESUMO

BACKGROUND: Pulmonary fibrosis is a progressive and irreversible disease for which therapeutic options are currently limited. A recent in vivo study showed that tenofovir, a nucleotide analogue reverse transcriptase inhibitor, had direct antifibrotic effects on skin and liver fibrosis. Another study in vitro revealed that NS5ATP9 inhibited the activation of human hepatic stellate cells. Because of the similarity of fibrotic diseases, we hypothesized that tenofovir alafenamide fumarate (TAF), the prodrug of tenofovir, and NS5ATP9, is related to and plays a role in the suppression of pulmonary fibrosis. METHODS: We investigated the influence of NS5ATP9 on fibrosis in vitro. Human lung fibroblasts (HFL1) were transfected with short interfering RNAs or overexpression plasmids of NS5ATP9 before stimulation by human recombinant transforming growth factor-ß1. The effect of TAF was evaluated in a bleomycin-induced fibrosis murine model. Male C57BL/6 mice were treated with bleomycin on day 0 by intratracheal injection and intragastrically administered TAF or vehicle. Left lung sections were fixed for histological analysis, while homogenates of the right lung sections and HFL1 cells were analyzed by western blotting and quantitative reverse transcription polymerase chain reaction. RESULTS: NS5ATP9 suppressed the activation of lung fibroblasts. Upregulation of collagen type 3 (α 1 chain) and α-smooth muscle actin was observed in HFL1 cells when NS5ATP9 was silenced, and vice-versa. TAF also showed anti-fibrotic effects in mice, as demonstrated by histological analysis of fibrosis and expression of extracellular matrix components in the lung sections. Additionally, TAF inhibited transforming growth factor-ß1 and phosphorylated-Smad3 synthesis in HFL1 cells and the murine model, which was accompanied by upregulation of NS5ATP9. CONCLUSIONS: Our results suggest that NS5ATP9 forms a negative feedback pathway in pulmonary fibrosis and TAF has anti-fibrotic properties as it upregulates the expression level of NS5ATP9. As TAF has been shown to be safe and well-tolerated in humans, TAF and NS5ATP9 may be useful for developing novel therapeutics for pulmonary fibrosis.


Assuntos
Adenina/análogos & derivados , Bleomicina/toxicidade , Proteínas de Ligação a DNA/biossíntese , Fibrose Pulmonar/metabolismo , Proteína Smad3/biossíntese , Fator de Crescimento Transformador beta1/biossíntese , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
14.
Am J Chin Med ; 47(5): 1113-1131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31352786

RESUMO

Pulmonary fibrosis (PF) is characterized by myofibroblast activation, which can be triggered by oxidative stress. In this study, we investigated the antifibrotic effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on PF and examined the underlying molecular mechanism. EASM suppressed myofibroblast activation with reduced extracellular matrix deposition in the lungs of mice subjected to bleomycin (BLM) challenge, demonstrating the inhibitory effects on PF. EASM positively alleviated oxidative stress by upregulating nuclear factor-erythroid 2-related factor 2 (Nrf2) and concomitantly downregulating NADPH oxidase 4 (Nox4) in the lungs of BLM-treated mice. This effect was also observed in an in vitro model of transforming growth factor beta 1 (TGF-ß1)-stimulated fibroblast activation. EASM reduced reactive oxygen species (ROS) generation in fibroblasts by stabilizing Nrf2 protein with promoting kelch-like ECH-associated protein 1 (Keap1) degradation. Nrf2 knockdown in the lungs of BLM-treated mice diminished the inhibitory effects of EASM on fibrosis, providing evidence in vivo to address the unique role of Nrf2. Additionally, EASM inhibited TGF-ß1/Smad3 signaling by downregulating protein kinase C delta (PKC-δ) and Smad3 phosphorylation (p-Smad3), which led to suppression of the TGF-ß1-induced fibrogenic response. These results indicate that EASM exhibits potent antifibrotic activity in vitro and in vivo, which might be associated with activation of Nrf2 pathway and inhibition of TGF-ß1/Smad3 pathway. Our findings support that EASM may act as an effective antifibrotic remedy for PF.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Salvia miltiorrhiza/química , Animais , Feminino , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , NADPH Oxidase 4/genética , Fator 2 Relacionado a NF-E2/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
15.
Respir Res ; 20(1): 168, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358001

RESUMO

BACKGROUND: Pulmonary fibrosis is a progressive disease characterized by structural distortion of the lungs. Transforming growth factor-beta (TGF-beta) is a key cytokine implicated in the pathogenesis of pulmonary fibrosis. TGF-beta-induced myofibroblast differentiation characterized by expression of smooth muscle alpha-actin and extracellular matrix proteins is a key process in pathogenesis of fibrotic disease. Tannic acid is a natural polyphenol with diverse applications. In this study, we investigated the effect of tannic acid on myofibroblast differentiation and pulmonary fibrosis in cultured cells and in bleomycin model of the disease. METHODS: Primary cultured human lung fibroblasts (HLF) were used. The relative levels of proteins were determined by Western blotting. HLF contraction was measured by traction microscopy. Bleomycin-induced pulmonary fibrosis in mice was used as the disease model. RESULTS: Tannic acid inhibited TGF-beta-induced expression of collagen-1 and smooth muscle alpha-actin (SMA) as well as force generation by HLF. Tannic acid did not affect initial phosphorylation of Smad2 in response to TGF-beta, but significantly inhibited sustained Smad2 phosphorylation, which we recently described to be critical for TGF-beta-induced myofibroblast differentiation. Accordingly, tannic acid inhibited Smad-dependent gene transcription in response to TGF-beta, as assessed using luciferase reporter for the activity of Smad-binding elements. Finally, in mouse model of bleomycin-induced pulmonary fibrosis, therapeutic application of tannic acid resulted in a significant reduction of lung fibrosis, decrease in collagen-1 content and of Smad2 phosphorylation in the lungs. CONCLUSIONS: This study demonstrates the anti-fibrotic effect of tannic acid in vitro and in vivo through a regulation of sustained Smad2 phosphorylation.


Assuntos
Antifibrinolíticos/farmacologia , Fibroblastos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Taninos/farmacologia , Animais , Antifibrinolíticos/uso terapêutico , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Pulmão/citologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/fisiologia , Taninos/uso terapêutico
16.
J Ethnopharmacol ; 243: 112096, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31323300

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Arenaria kansuensis is used in traditional medicine to treat lung inflammation for a long time. However, the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of this plant have not been studied extensively. AIM OF THE STUDY: The purpose of this study was to investigate the anti-pulmonary fibrosis effect and its corresponding bioactive constituents of A. kansuensis and its possible mechanism. MATERIALS AND METHODS: In vivo experiment, the anti-pulmonary fibrosis effects of the fraction (Part1) enriched from ethyl acetate extracts of the whole plant A. kansuensis were evaluated through bleomycin (BLM)-induced pulmonary fibrosis mice (five groups, n = 10) daily at doses of 50, 100 and 150 mg/kg for 15 days. In vitro experiment, the anti-inflammation and reversed epithelial-mesenchymal transition (EMT) effect of 12 ß-carboline alkaloids isolated from Part1 were evaluated through lipopolysaccharide (LPS)-induced RAW264.7 inflammatory cell model and TGF-ß1 induced A549 cell model. RESULTS: In this study, a fraction named Part1 extracted from Arenaria kansuensis presented strong anti-pulmonary fibrosis effect at the dose of 150 mg/kg. Vivo experiments showed that the survival rate and body weight of mice significantly increased after Part1 treatment. Part1 could significantly inhibit the initial of inflammation, deposition of collagen and expression of TGF-ß1 and α-SMA, moreover, the expression of E-cadherin was significantly elevated after administration of Part1. All the cure effects of Part1 were in dose dependent manner. A total of 12 ß-carboline alkaloids were identified in Part1 and they all showed suppressive effect on inflammatory cytokines including MCP-1, TNF-α, IL-6 and IL-1ß through inhibition of NF-kb/p65 phosphorylation, and that epithelial-mesenchymal transition (EMT) process was reversed by different compounds in different levels. The expression of indicators of EMT including α-SMA, vimentin and E-cadherin was significantly improved after given different ß-carboline alkaloids. CONCLUSIONS: This study showed that antifibrogenic effect of ß-carboline alkaloids was due to inhibiting the initial of inflammation through NF-kb/p65 pathway and reversing the process of EMT.


Assuntos
Alcaloides , Anti-Inflamatórios , Arenaria (Planta) , Carbolinas , Extratos Vegetais , Fibrose Pulmonar/tratamento farmacológico , Alcaloides/farmacologia , Alcaloides/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Bleomicina , Carbolinas/farmacologia , Carbolinas/uso terapêutico , Linhagem Celular , Citocinas/genética , Citocinas/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/metabolismo
17.
Cell Tissue Res ; 378(2): 255-265, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31214773

RESUMO

Fibrosis in the lungs usually occurs in the initial phase of acute respiratory distress syndrome (ARDS), which exacerbates poor prognosis among patients. MicroRNAs (miRs) have the ability to modulate the expression profiles of many genes, thus essentially altering cell phenotypes. We hypothesize that miRs may be involved in the development of lung fibrosis in mice. In this study, mice were treated with lipopolysaccharide (LPS) to establish the lung fibrosis animal model. Hematoxylin and eosin (H&E) staining and western blot (WB) were performed to confirm the successful establishment of the model. Quantitative PCR (qPCR) and WB were utilized to monitor the expression of miRs and proteins. A dual-luciferase reporter assay was used to detect the interaction between miR and genes. We observed miR-506 downregulation in lung tissues during lung fibrosis after ARDS rat modeling by LPS exposure. We also observed that its expression level was similar to that observed in TGF-ß1-induced human MRC-5 cells. The proportion of apoptotic cells decreased, while levels of inflammatory cytokines were upregulated in lung tissues during lung fibrosis and in fibroblasts after TGF-ß1 treatment. In order to elucidate the possible role of miR-506, it was overexpressed in mice with ARDS. It was revealed that miR-506 significantly ameliorated the degree and spread of pulmonary damage stimulated by LPS. miR-506 also induced apoptosis in vivo and in vitro, while also ameliorating the inflammatory response. Notably, p65, a subunit of NF-κB, acts as a target of miR-506. p65 expression was downregulated in TGF-ß1-treated MRC-5 cells upon transfection with miR-506 mimic. Indeed, the 3'-UTR of human p65 contained functional human miR-506-responsive sequences. LPS induction and TGF-ß1 stimulation in mice led to p65 upregulation. In addition, p65 knockdown in the ARDS mouse model partially ameliorated the severity of lung lesions, induced apoptosis and reduced inflammation in lung tissue. Our findings revealed that miR-506 could be an important modulator of apoptosis and inflammation and a regulator of lung fibrosis.


Assuntos
Citocinas/metabolismo , Pulmão , MicroRNAs/fisiologia , Fibrose Pulmonar/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Apoptose , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Ratos
18.
J Pharm Pharmacol ; 71(8): 1301-1310, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215034

RESUMO

OBJECTIVES: The present study investigated the effects of atorvastatin on kidney injury in mice with pulmonary fibrosis (PF). METHODS: Adult mice were divided into four groups: mice treated with intratracheal bleomycin (I) and their controls (II), and mice treated with atorvastatin for 10 days after 7 days from bleomycin treatment (III) and their controls (IV). Mice were dissected on the 21st day. KEY FINDINGS: Mononuclear cell infiltrations, injured proximal tubule epithelium and p-c-Jun level increased, while cell proliferation and the levels of p-SMAD2, ELK1, p-ELK1, p-ATF2 and c-Jun decreased in the kidney tissue of mice with PF. The atorvastatin treatments to mice with PF resulted in significant increases at the TGF-ß activation, cell proliferation and kidney damage and decreases in the levels of p-SMAD2, p-ELK1, p-ATF2 and p-c-Jun, but not change the p-SMAD3, ELK1 and ATF2 in kidneys. CONCLUSIONS: The depletion of MAPK signals, rather than SMAD signalling, is effective in kidney damage of mice with PF. Atorvastatin did not regress kidney damage in these mice, whereas it increases the kidney injury. The c-Jun-mediated JNK signals could help kidney repair through cell proliferation. The treatment time and doses of atorvastatin should be optimized for regression of kidney damage.


Assuntos
Atorvastatina/farmacologia , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Fibrose Pulmonar/metabolismo , Animais , Bleomicina/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos
19.
Toxicol Lett ; 313: 30-41, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181250

RESUMO

The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Diferenciação Celular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Fibrose Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/prevenção & controle , Adulto , Idoso , Animais , Antracose/metabolismo , Antracose/patologia , Linhagem Celular , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Silicose/patologia
20.
Cell Mol Life Sci ; 76(23): 4783-4794, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31168659

RESUMO

RATIONALE: Mitochondrial homeostasis has recently emerged as a focal point in the pathophysiology of idiopathic pulmonary fibrosis (IPF), but conflicting data have been reported regarding its regulation. We speculated that phosphoglycerate mutase family member 5 (PGAM5), a mitochondrial protein at the intersection of multiple cell death and mitochondrial turnover pathways, might be involved in the pathogenesis of IPF. METHODS: PGAM5-deficient mice and human pulmonary epithelial cells were analyzed comparatively with PGAM5-proficient controls in a bleomycin-based model of pulmonary fibrogenesis. Mitochondria were visualized by confocal and transmission electron microscopy. Mitochondrial homeostasis was assessed using JC1 (ΔΨ) and flow cytometry. RESULTS: PGAM5 plays an important role in pulmonary fibrogenesis. Pgam5-/- mice displayed significantly attenuated lung fibrosis compared to controls. Complementary, in vitro studies demonstrated that PGAM5 impaired mitochondrial integrity on a functional and structural level independently of mtROS-production. On a molecular level, reduced mitophagy caused by PGAM5 deficiency improved mitochondrial homeostasis. CONCLUSIONS: Our study identifies PGAM5 as an important regulator of mitochondrial homeostasis in pulmonary fibrosis. Our data further indicate PGAM5-mediated mitophagy itself as a pivotal gateway event in the mediation of self-sustaining mitochondrial damage and membrane depolarization. Our work hereby highlights the importance of mitochondrial dynamics and identifies a potential therapeutic target that warrants further studies. Toxic agents lead to mitochondrial damage resulting in depolarization of the mitochondrial membrane potential (ΔΨ) which is a gateway event for the initiation of PGAM5-mediated mitophagy. PGAM5-mediated mitophagy in turn leads to a self-perpetuating escalation of ΔΨ depolarization. Loss of the mitophagy-based damage-enhancing loop under PGAM5-deficient conditions breaks this vicious cycle, leading to improved mitochondrial homeostasis.


Assuntos
Mitocôndrias/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fibrose Pulmonar/patologia , Células A549 , Animais , Bleomicina/farmacologia , Modelos Animais de Doenças , Edição de Genes , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/efeitos dos fármacos , Fosfoproteínas Fosfatases/genética , Proteínas Quinases/metabolismo , Fibrose Pulmonar/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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