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1.
Toxicol Lett ; 323: 57-66, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32017981

RESUMO

Oxidative stress and inflammatory processes are proposed to mediate the development of silicosis. However, antioxidant therapy has not produced consistent results during the treatment of silicosis. α-Lipoic acid synthesized by lipoic acid synthase is a powerful anti-oxidant and helps protect mitochondria. Thus far, the effect of endogenous α-Lipoic acid on silicosis has not been elucidated yet. We established an experimental model of silicosis with wildtype and LiasH/H mice, a new antioxidant mouse model which has overexpressed Lias gene (∼150 %) relative to its wild type counterpart. We systemically examined main pathological changes of pulmonary fibrosis, and explored α-lipoic acid effects on oxidative stress, inflammatory and pulmonary fibrosis biomarkers in silica-instillated mice. In LiasH/H mice over-expression of lipoic acid alleviated the severity of major pathological alterations in the early stage of pulmonary fibrosis induced by silica compared with wild type mice. Silica significantly increased oxidative stress in both wild type and LiasH/H mice. The antioxidant defense was strengthen including increased NRF2 and LIAS production in LiasH/H mice. Relieved oxidative stress resulted in decreased inflammatory response and secretion of chemokines. LiasH/H mice reduced chronic inflammatory response and inhibition of NF-κB activity after silica instillation. The LiasH/H mouse model overexpression of lipoic acid synthase gene retarded the development of silica-induced pulmonary fibrosis. Strengthen antioxidant defense by increased lipoic acid synthase is a potential strategy for protection against silica-induced pulmonary fibrosis.


Assuntos
Fibrose Pulmonar/induzido quimicamente , Dióxido de Silício/toxicidade , Sulfurtransferases/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/fisiologia , NF-kappa B/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Fator de Crescimento Transformador beta1/fisiologia
2.
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
3.
BMJ ; 367: l5553, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641045

RESUMO

Sarcoidosis is a highly variable granulomatous multisystem syndrome. It affects individuals in the prime years of life; both the frequency and severity of sarcoidosis are greater in economically disadvantaged populations. The diagnosis, assessment, and management of pulmonary sarcoidosis have evolved as new technologies and therapies have been adopted. Transbronchial needle aspiration guided by endobronchial ultrasound has replaced mediastinoscopy in many centers. Advanced imaging modalities, such as fluorodeoxyglucose positron emission tomography scanning, and the widespread availability of magnetic resonance imaging have led to more sensitive assessment of organ involvement and disease activity. Although several new insights about the pathogenesis of sarcoidosis exist, no new therapies have been specifically developed for use in the disease. The current or proposed use of immunosuppressive medications for sarcoidosis has been extrapolated from other disease states; various novel pathways are currently under investigation as therapeutic targets. Coupled with the growing recognition of corticosteroid toxicities for managing sarcoidosis, the use of corticosteroid sparing anti-sarcoidosis medications is likely to increase. Besides treatment of granulomatous inflammation, recognition and management of the non-granulomatous complications of pulmonary sarcoidosis are needed for optimal outcomes in patients with advanced disease.


Assuntos
Glucocorticoides/uso terapêutico , Hipertensão Pulmonar/prevenção & controle , Imunossupressores/uso terapêutico , Fibrose Pulmonar/prevenção & controle , Sarcoidose Pulmonar/diagnóstico , Biomarcadores/sangue , Broncoscopia/métodos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Fluordesoxiglucose F18/administração & dosagem , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/mortalidade , Incidência , Pulmão/diagnóstico por imagem , Pulmão/patologia , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/mortalidade , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/tratamento farmacológico , Sarcoidose Pulmonar/epidemiologia , Resultado do Tratamento
4.
Appl Microbiol Biotechnol ; 103(20): 8559-8569, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473797

RESUMO

Phycocyanin (PC) is a light-harvesting protein isolated from Spirulina and has health benefits for a range of diseases including pulmonary fibrosis (PF). In this study, a bleomycin-induced pulmonary fibrosis model was used to determine whether PC attenuates PF and modulates the intestinal microbiota. The results showed that PC intervention attenuated the pulmonary fibrosis, demonstrated by hematoxylin-eosin staining (HE), Masson's trichrome staining, and lung dry-wet weight ratio, and PC significantly inhibited the production of interleukin-1 beta (IL-1ß), tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS). Additionally, intestinal microbiota analysis revealed that PC intervention significantly increased the bacterial diversity and richness. Correlation analysis indicated that 9 families and 17 genes were significantly associated with at least 1 physiological index. And PC intervention significantly decreased the bacteria which is related to inflammation and dramatically increased the SCFAs-producing bacteria and probiotics. These data indicated that PC can decrease the pro-inflammatory cytokines and regulate the intestinal microbiota in BLM-induced PF mice.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Ficocianina/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Animais , Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Histocitoquímica , Pulmão/patologia , Camundongos Endogâmicos C57BL , Resultado do Tratamento
5.
DNA Cell Biol ; 38(12): 1418-1426, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31560574

RESUMO

Silicosis is an occupational disease characterized as inflammatory cells infiltration and severe progressive pulmonary fibrosis. Kaempferol (Kae), a flavonoid that exists in many plants and fruits, has been proved to have anti-inflammatory and antifibrosis functions. However, the effects of Kae on silicosis remain unclear. In the present study, we analyzed the therapeutic effects of Kae in 1-, 7-, and 28-day silicosis models, respectively. In the 1-day model, Kae treatment did not vary the wet-to-dry weight ratios of the lung, apoptotic rate, autophagy, or the expression of inflammatory factors. In contrast, Kae significantly inhibited pulmonary inflammation in the 7-day silicosis models and inhibited silica-induced pulmonary fibrosis in the 28-day models. Besides, we found that Kae partially restored silica-induced LC3 lipidation without increasing the p62 levels. Blocking autophagy with chloroquine antagonized the inhibitory effects of Kae on inflammation, suggesting that autophagy might be required in the therapeutic effects of Kae on silicosis. These findings indicated that Kae inhibits the progression of silica-induced pulmonary fibrosis, which may provide experimental evidences for Kae in the treatment of silicosis.


Assuntos
Autofagia , Modelos Animais de Doenças , Quempferóis/farmacologia , Fibrose Pulmonar/prevenção & controle , Dióxido de Silício/efeitos adversos , Silicose/prevenção & controle , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Silicose/etiologia
6.
Toxicol Lett ; 313: 178-187, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284023

RESUMO

Long-term inhalation of crystalline silica particles leads to silicosis characterized by pulmonary inflammation and interstitial fibrosis. The growth arrest-specific protein 6 (Gas6) and its tyrosine receptor Mer have been implicated to involve in the regulation of inflammation, innate immunity and tissue repair. However, the role of Gas6 or Mer in silica-induced lung inflammation and fibrosis has not been investigated previously. In this study, we observed a remarkable increase of Gas6 in bronchoalveolar lavage fluid (BALF) from wild-type C57BL/6 mice after silica intratracheal administration. Then, we investigated whether genetic loss of Gas6 or Mer could attenuate silica-induced lung inflammation and fibrosis. Our results showed that Gas6-/- and Mer-/- mice exhibited reduced lung inflammation response from days 7 to 84 after silica exposure. We also uncovered an overexpression of the suppressor of cytokine signaling protein 1 in silica-treated deficient mice. Moreover, Gas6 or Mer deficiency attenuated silica-induced collagen deposition by inhibiting the expression of transforming growth factor-ß. We conclude that gene absence of Gas6 or Mer is protective against silica-induced lung inflammation and fibrosis in mice. Targeting Gas6/Mer pathway may be a potential therapeutic approach to treat pulmonary fibrosis in patients with silicosis.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Pulmão/enzimologia , Pneumonia/prevenção & controle , Fibrose Pulmonar/prevenção & controle , Silicose/prevenção & controle , c-Mer Tirosina Quinase/deficiência , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intercelular/genética , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/enzimologia , Pneumonia/genética , Pneumonia/patologia , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Transdução de Sinais , Silicose/enzimologia , Silicose/genética , Silicose/patologia , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , c-Mer Tirosina Quinase/genética
7.
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
8.
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
9.
Biomed Pharmacother ; 115: 108955, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31075733

RESUMO

Radiation-induced pulmonary fibrosis (RIPF) is a severe complication in patients treated with thoracic irradiation. Until now, there are no effective therapeutic drugs for RIPF. In the present study, we attempted to evaluate the effect of Magnesium isoglycyrrhizinate (MgIG) on RIPF, and to further explore the underlying mechanisms. We found that MgIG treatment markedly improved radiation-induced lung pathological changes, reduced collagen deposition, and decreased the transforming growth factor beta1 (TGF-ß1) elevation induced by irradiation. In addition, MgIG treatment significantly relieved oxidative damage of pulmonary fibrosis in mice characterized by increased antioxidant factors expression and reduced oxidative factors expression. And, MgIG treatment also significantly reduced the production of intracellular reactive oxygen species (ROS) in vitro. Interestingly, administration of MgIG achieved lower expression levels of Nox4, and phosphorylation of p38MAPK and Akt in vivo and in vitro. Furthermore, treatment with MgIG notably reduced the expression levels of myofibroblast markers, Nox4, and phosphorylation of p38MAPK and Akt both in vivo and in vitro. More importantly, the inhibitory effects of MgIG on fibroblast differentiation were enhanced when the p38MAPK/Akt/Nox4 pathway was inhibited using their respective antagonists or Nox4 siRNA in vitro. Taken together, these findings suggested that MgIG could attenuate RIPF partly by inhibiting fibroblast differentiation, which was closely related to modulation of the p38MAPK/Akt/Nox4 pathway.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Pulmão/metabolismo , Fibrose Pulmonar/prevenção & controle , Lesões Experimentais por Radiação/prevenção & controle , Saponinas/farmacologia , Triterpenos/farmacologia , Animais , Linhagem Celular , Medicamentos de Ervas Chinesas , Feminino , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Raios gama , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Int J Mol Med ; 44(1): 227-239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115492

RESUMO

Endoplasmic reticulum (ER) stress in alveolar epithelial cells (AECs) is associated with the pathogenesis of pulmonary fibrosis. Bone marrow­derived mesenchymal stromal cells (BM­MSCs) can exert protective effects on ER­stressed AECs via paracrine signaling. In the present study, mouse lung epithelial (MLE)­12 cells were directly stimulated with various concentrations of bleomycin (BLM). MLE­12 cell apoptosis was detected by flow cytometry, and Ki67 expression was detected by immunofluorescence to reflect cell proliferation. The results revealed that BLM increased the protein expression levels of X­box binding protein 1 and immunoglobulin heavy chain­binding protein, thus inducing ER stress, and caused cell dysfunction by inhibiting proliferation and promoting apoptosis. In addition, MSC­derived conditioned medium (MSC­CM) protected MLE­12 cells from BLM­induced injury, by reducing ER stress, promoting cell proliferation and inhibiting cell apoptosis. Our previous studies reported that N­methyl­D­aspartate (NMDA) receptor activation partially inhibits the antifibrotic effect of BM­MSCs on BLM­induced pulmonary fibrosis through downregulating the paracrine factor hepatocyte growth factor (HGF). In the present study, the synthesis and secretion of HGF were detected by western blotting and ELISA, respectively. Results further demonstrated that NMDA inhibited the synthesis and secretion of HGF in BM­MSCs, and NMDA­preconditioned MSC­CM had no protective effects on BLM­induced injury in MLE­12 cells. In addition, activation of the NMDA receptor decreased the phosphorylation levels of extracellular signal­regulated kinase (ERK)1/2 in BM­MSCs. Using Honokiol and FR180204, the activator and inhibitor of ERK1/2, respectively, it was then revealed that Honokiol partially eliminated the decrease in HGF expression, whereas FR180204 further promoted the reduction in HGF caused by NMDA. Collectively, these findings suggested that NMDA receptor activation may downregulate HGF by inhibiting ERK signaling in BM­MSCs, thus weakening their protective effects on BLM­induced lung epithelial cell damage.


Assuntos
Células Epiteliais Alveolares/metabolismo , Bleomicina/efeitos adversos , Células da Medula Óssea/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina , Fibrose Pulmonar/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Bleomicina/farmacologia , Células da Medula Óssea/patologia , Linhagem Celular , Feminino , Células-Tronco Mesenquimais/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle
11.
Biomed Pharmacother ; 115: 108870, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31026730

RESUMO

Idiopathic Pulmonary fibrosis (IPF) is diagnosed as a life-threatening, progressive and incurable lung disease characterized by accumulation of extracellular matrix and myofibroblasts, resulting in the function degradation and structural alterations in normal lung parenchyma. Notably, Pulmonary Fibrosis has been considering as a difficult problem in clinical with high mortality and effective treatment strategies. Rosavin, a benzylPropylene glycoside, is isolated from Rhodiola rosea L., exhibiting nootropic, anti-depressant, anti-cancer, anti-inflammatory and anti-oxidative activities. In this study, we attended to elucidate the pharmacological activity of Rosavin for treatment of pulmonary fibrosis induced by bleomycin in mice. The results indicated that Rosavin could significantly ameliorate the lung index and Pathological structure of mice with Pulmonary fibrosis by bleomycin-induced. Additionally, Rosavin could evidently decreased inflammatory cells infiltration in bronchoalveolar lavage fluid and pro-inflammatory cytokines expression in lung tissue specimens induced by bleomycin. Rosavin could down-regulate the expression of hydroxyproline and malondialdehyde and increased the activities of superoxide dismutase, glutathione peroxidase in lung tissue. The expression of Nrf2 were increased, and the expression of NF-κB p65, TGF-ß1 and α-SMA were inhibited. The findings revealed the protective effects and the primary mechanism of rosavin on bleomycin-induced pulmonary fibrosis, which provided a scientific foundation for Rosavin as a promising candidate for Pulmonary fibrosis treatment.


Assuntos
Bleomicina/toxicidade , Dissacarídeos/farmacologia , Inflamação/prevenção & controle , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Animais , Antibióticos Antineoplásicos/toxicidade , Citocinas/genética , Citocinas/metabolismo , Dissacarídeos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Camundongos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Organismos Livres de Patógenos Específicos
12.
Toxicol Lett ; 311: 1-10, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31028789

RESUMO

Pulmonary fibrosis induced by prolonged exposure to silica particles is a chronic and irreversible lung disease without effective treatment till now. Our previous study has shown that early intervention with MARCO antagonist PolyG could alleviate pulmonary fibrosis in silica-exposed rats. However, the therapeutic effects of PolyG on silica-induced pulmonary fibrosis have rarely been reported. In this study, we explored the effects of administration (on the 28th day after silica exposure) of PolyG (MARCO inhibitor) on an established rat silicosis model. The lungs were analyzed histopathologically in rats using HE and Masson staining. The silica-induced ERS-related apoptosis, EMT and fibrosis were evaluated using western blotting, qRT-PCR and immunohistochemical analyses. The results suggested that silica exposure could increase the MARCO activity, and induce ERS and EMT in lung tissues. Pharmacological targeting of MARCO with PolyG attenuated the development of pulmonary fibrosis in silica-exposed rats. Further study indicated that PolyG could inhibit silica-induced ERS-related apoptosis and EMT process. Together, our findings reveal an essential function of ERS-related apoptosis and EMT in the processes of pulmonary fibrosis caused by silica, and identify MARCO as a potential therapeutic pharmacological target for silicosis.


Assuntos
Pulmão/efeitos dos fármacos , Poli G/farmacologia , Fibrose Pulmonar/prevenção & controle , Receptores Imunológicos/antagonistas & inibidores , Fármacos do Sistema Respiratório/farmacologia , Dióxido de Silício , Silicose/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ligantes , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Silicose/patologia
13.
Am J Med Sci ; 357(6): 483-491, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31000424

RESUMO

BACKGROUND: Individuals with HIV have ∼2-fold increased risk of developing pulmonary fibrosis. The mechanism(s) by which this occurs has yet to be determined. HIV-1 protein gp120 activates CXCR4 in the lymphocyte, promoting a variety of intracellular signaling pathways including those common to TGFß1 associated with lung fibroblast-to-myofibroblast transdifferentiation. We hypothesized that gp120 promotes pulmonary fibrotic changes via activation of CXCR4 in the lung fibroblast. METHODS: Mouse primary lung fibroblasts (PLFs) were cultured ± gp120, then analyzed for α-SMA expression and stress fiber formation. In parallel, PLFs were cultured ± gp120 ± AMD3100 (a CXCR4 antagonist), and α-SMA, pan and phospho-Akt, and total and phospho-MAPK (or ERK1/2) protein expression was quantified. Finally, lungs and PLFs from wild-type and HIV-1 transgenic mice were analyzed for hydroxyproline and α-SMA content. RESULTS: gp120 treatment increased α-SMA expression and myofibroblast differentiation in PLFs. gp120 treatment activated phosphorylation of ERK1/2, but not PI3K-Akt. Pretreatment with AMD3100 inhibited gp120-induced ERK1/2 phosphorylation and gp120-induced α-SMA expression. In parallel, there was a significant increase in hydroxyproline content in lungs from older HIV-1 transgenic mice and a >3-fold increase in α-SMA expression in PLFs isolated from HIV-1 transgenic mice. CONCLUSIONS: gp120 induces α-SMA expression and fibroblast-to-myofibroblast transdifferentiation by activating the CXCR4-ERK1/2 signaling pathway in mouse PLFs. Lungs of older HIV-1 transgenic mice contain higher hydroxyproline content and their PLFs have a striking increase in α-SMA expression. These results suggest a mechanism by which individuals with HIV are at increased risk of developing pulmonary fibrotic changes as they age.


Assuntos
Transdiferenciação Celular , Fibroblastos/metabolismo , Proteína gp120 do Envelope de HIV/fisiologia , Fibrose Pulmonar/etiologia , Receptores CXCR4/metabolismo , Actinas/metabolismo , Animais , Feminino , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Hidroxiprolina/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos Transgênicos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Receptores CXCR4/antagonistas & inibidores
14.
Artigo em Chinês | MEDLINE | ID: mdl-30884583

RESUMO

Objective: To observe the repairing effect of adipose mesenchymal stem cells (ADSCs) on lung injury induced by silica in rats. Methods: Primary ADSCs-GFP was obtained from rats. ADSCs-GFP was injected into tail vein of silicosis model rats. The expression of green fluorescence in lungs was observed regularly to determine the homing ability of ADSCs. Primary ADSCs of rats were obtained and randomly divided into control group, exposure group, vehicle group and ADSCs group. Silicosis rat model was established by non-exposed tracheal drip method. 24 hours after silica exposure, rats in ADSCs group were injected with ADSCs of 1×10(6)/kg body weight through tail vein, and the pathological changes of lung tissue were observed and evaluated 28 days after intervention. To explore the early intervention mechanism of ADSCs on pulmonary fibrosis in silicosis model rats, apoptosis-related proteins were detected by immunohistochemistry. Results: 28 days after exposure to silica, rats in the exposure group showed obvious pulmonary fibrosis. Compared with exposure group and vehicle group, ADSCs group showed less pulmonary inflammation, less silica nodules and less collagen deposition area. Immunohistochemical results showed that the expression of Caspase-3 and cytochrome C protein decreased and Bcl-2 protein increased after ADSCs transplantation. Conclusion: ADSCs infusion has an obvious intervention effect on postponing early silicosis fibrosis in rats exposed to silica, and its mechanism is related to the regulation of apoptotic process.


Assuntos
Tecido Adiposo/citologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/prevenção & controle , Células-Tronco Mesenquimais/metabolismo , Dióxido de Silício/toxicidade , Animais , Modelos Animais de Doenças , Fibrose Pulmonar/prevenção & controle , Distribuição Aleatória , Ratos , Silicose/prevenção & controle
15.
Biomed Pharmacother ; 113: 108768, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30889486

RESUMO

Pulmonary fibrosis (PF) progression may be involved with arginine (Arg) metabolism and immune balance. The present study aimed to explore the effects of L-Arginine (L-Arg) and L-Norvaline (L-Nor) on bleomycin (BLM)-induced PF in mice, meanwhile, and observe dynamic changes of Arg metabolism, immune balance and crosstalk between them in PF progression. Followed intratracheal instillation of BLM or saline, Kunming mice were treated orally with saline, L-Arg, L-Nor and L-Arg + L-Nor three times a day. And the mice were sacrificed on Day 3, 14 and 28 after treatment. Changes of body weight, lung index, lung hydroxyproline and histopathology were analyzed to evaluate the PF degree. Peripheral blood Arg, Citrulline (Cit), Ornithine (Orn) and Proline (Pro), lung NO, NOS and arginase were analyzed to evaluate the Arg metabolism. Peripheral blood Tregs, Th17 and γδT cells were analyzed to evaluate the immune balance. Our data showed that combination of L-Arg and L-Nor dynamically reversed the weight loss, decreased lung index and hydroxyproline, and improved lung histopathological damages induced by BLM. The combination dynamically and significantly rectified Tregs, Th17, γδT and Tregs/Th17 abnormal changes. Meanwhile, these disorders of peripheral blood Arg, Cit, Orn, Pro, Orn/Cit and Pro/Orn, and lung NO, iNOS and TNOS were also improved accordingly. These results demonstrated that combination of L-Arg and L-Nor had inhibitory effects on BLM-induced PF progression, possibly due to their corrective action on immune imbalance, Arg metabolism disorder and crosstalk abnormality in the progression of PF.


Assuntos
Arginina/administração & dosagem , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Valina/análogos & derivados , Administração Oral , Animais , Arginina/farmacologia , Bleomicina/toxicidade , Modelos Animais de Doenças , Progressão da Doença , Quimioterapia Combinada , Linfócitos Intraepiteliais/imunologia , Pulmão/patologia , Masculino , Camundongos , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Valina/administração & dosagem , Valina/farmacologia
16.
Clin Sci (Lond) ; 133(7): 789-804, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902828

RESUMO

Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-κB pathway and production of pro-inflammatory cytokine IL-6 in lung epithelial cells. ANXA2-deficient (ANXA2-/-) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.


Assuntos
Anexina A2/metabolismo , Bleomicina , Pulmão/metabolismo , Pneumonia/metabolismo , Fibrose Pulmonar/metabolismo , Células A549 , Animais , Anexina A2/antagonistas & inibidores , Anexina A2/genética , Modelos Animais de Doenças , Exossomos/metabolismo , Humanos , Interleucina-6/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Pneumonia/induzido quimicamente , Pneumonia/patologia , Pneumonia/prevenção & controle , Transporte Proteico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Venenos de Escorpião/farmacologia
17.
J Pharm Pharmacol ; 71(6): 1017-1028, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30847938

RESUMO

OBJECTIVES: Investigating the antipulmonary fibrosis effect of mangiferin from Mangifera indica and the possible molecular mechanism. METHODS: In vivo, bleomycin (BLM)-induced pulmonary fibrosis experimental model was used for evaluating antipulmonary fibrosis effect of mangiferin. Histopathologic examination and collagen deposition were investigated by HE and Masson staining as well as detecting the content of hydroxyproline. The expression of transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), TLR4 and p-P65 in lung tissue was analysed through immunofluorescence. Leucocytes and inflammatory cytokines including IL-1ß, IL-6, TNF-α and MCP-1 in bronchoalveolar lavage fluid were detected by cell counting and enzyme-linked immunosorbent assay. In vitro, TGF-ß1-induced A549 epithelial-mesenchymal transition (EMT) cell model was used for investigating the possible molecular mechanism. Reactive oxygen species (ROS) generation was detected by DCFH-DA assay. Expression of all proteins was examined by Western blot. KEY FINDINGS: Oral administration of mangiferin could attenuate the severity of BLM-induced pulmonary fibrosis through increasing the survival rate, improving histopathological lesion and body weight loss as well as decreasing pulmonary index visibly. Pulmonary hydroxyproline content, TGF-ß1, and α-SMA levels were reduced significantly. The molecular mechanism of mangiferin for inhibiting pulmonary fibrosis is that it could obviously inhibit the occurrence of inflammation and the secretion of inflammatory cytokine through inhibiting activation of TLR4 and phosphorylation of p65. Meanwhile, EMT process was suppressed obviously by mangiferin through blocking the phosphorylation of Smad2/3 and reducing MMP-9 expression. Besides, mangiferin could significantly inhibit the process of oxidant stress through downregulating the intracellular ROS generation. CONCLUSIONS: Mangiferin attenuates BLM-induced pulmonary fibrosis in mice through inhibiting TLR4/p65 and TGF-ß1/Smad2/3 pathway.


Assuntos
Mangifera/classificação , Estresse Oxidativo/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Xantonas/farmacologia , Células A549 , Animais , Bleomicina/toxicidade , Líquido da Lavagem Broncoalveolar , Colágeno/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Xantonas/isolamento & purificação
18.
Int J Rheum Dis ; 22(4): 686-694, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30666825

RESUMO

AIM: To investigate the potential therapeutic efficacy of iguratimod (IGU) on bleomycin (BLM)-induced pulmonary fibrosis in mice. METHODS: A total of 75 C57BL/6 mice were randomly and evenly divided into control group, BLM (5 mg/kg) group, BLM + IGU (90 mg/kg) group, BLM + methylprednisolone (MP, 10 mg/kg) group and BLM + pirfenidone (PF, 100 mg/kg) group. The mice were sacrificed on day 7, 14 and 28. The lung tissue was examined by hematoxylin and eosin staining and Masson staining to evaluate the degree of alveolitis and fibrosis, and serum cytokines were measured. RESULTS: Histopathological results showed that IGU attenuated BLM-induced alveolar inflammation and decreased collagen deposition in lung tissue from day 7 till day 28. Both the pathological alveolitis and fibrosis scores in the drug-treated groups (IGU group, MP group and PF group) were decreased dramatically compared with the BLM group on day 7, 14 and 28 (P < 0.05). There were no statistical significances among these three groups. Cytokine profile showed that IGU decreased the level of tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6 and matrix metalloproteinase (MMP)-9 which were up-regulated by BLM on day 7, 14 and 28 (P < 0.05). Furthermore, there is a strong correlation between the severity of pulmonary fibrosis and serum MMP-9 levels. CONCLUSION: IGU can decrease BLM-induced pulmonary fibrosis, and the anti-fibrotic effect of IGU is mediated partly via inhibition of MMP-9, which suggests that IGU could potentially be an effective therapeutic strategy for pulmonary fibrosis.


Assuntos
Anti-Inflamatórios/farmacologia , Bleomicina , Cromonas/farmacologia , Colágeno/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Pneumonia/prevenção & controle , Alvéolos Pulmonares/efeitos dos fármacos , Fibrose Pulmonar/prevenção & controle , Sulfonamidas/farmacologia , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Citocinas/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/enzimologia , Pneumonia/patologia , Alvéolos Pulmonares/enzimologia , Alvéolos Pulmonares/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/enzimologia , Fibrose Pulmonar/patologia
19.
Am J Respir Cell Mol Biol ; 60(1): 41-48, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130411

RESUMO

Severe pulmonary fibrosis such as idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix and fibroblast activation. Targeting fibroblast activation has contributed to the development of antifibrotic therapeutics for patients with IPF. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), downstream in the transforming growth factor-ß/p38 mitogen-activated protein kinase pathway, has been implicated in inflammatory and fibrosing diseases. Increased concentrations of activated MK2 were expressed in IPF lung and in the mouse bleomycin model of lung fibrosis. The aim of the present study was to determine the role and the mechanisms of MK2 in fibroblast invasion and lung fibrosis. Our results showed that an MK2 inhibitor (MMI-0100) was able to inhibit the invasive capacity of lung fibroblasts isolated from patients with IPF, as well as fibroblasts isolated from both wild-type mice and mice with overexpressing hyaluronan synthase 2 (HAS2) in the myofibroblast compartment. We previously showed that hyaluronan and HAS2 regulate fibroblast invasion and lung fibrosis in vivo. The results of the present study showed that MMI-0100 reduced transforming growth factor-ß-induced hyaluronan production in human and mouse fibroblasts in vitro and that HAS2 mediated MK2 activation, suggesting a feed-forward loop in fibroblast activation. More importantly, MK2 inhibition attenuated hyaluronan accumulation and reduced collagen content in bleomycin-injured mouse lungs in vivo. Conditional deletion of MK2 in fibroblasts attenuated bleomycin-induced lung fibrosis. These data provide evidence that MK2 has a role in fibroblast invasion and fibrosis and may be a novel therapeutic target in pulmonary fibrosis.


Assuntos
Fibroblastos/patologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Fibrose Pulmonar/prevenção & controle , Índice de Gravidade de Doença , Animais , Antibióticos Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Bleomicina/toxicidade , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
20.
Int J Radiat Oncol Biol Phys ; 103(1): 208-216, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171878

RESUMO

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a severe and life-threatening complication of radiation therapy in patients with thoracic cancer; however, the exact molecular mechanisms remain unknown, and there is no effective treatment method in clinic. Here, we assessed the role of follistatin-like 1 (Fstl1) in RIPF. METHODS AND MATERIALS: Protein and messenger RNA levels of Fstl1 in lung tissues from symptomatic RIPF patients, Rhesus macaques, and mice were assessed. Fibrotic and inflammatory responses to radiation-induced lung injury and accumulation of myofibroblasts in Fstl1 haplodeficient (Fstl1+/-) mice were determined. Finally, radiation-induced differentiation and activation of fibroblasts in primary Fstl1+/- lung fibroblasts were evaluated. RESULTS: FSTL1 amounts were significantly increased in serum and/or radiation-injured lung specimens from symptomatic RIPF patients, Rhesus macaques, and mice. Haplodeletion of Fstl1 in Fstl1+/- mice was protective against x-ray-induced lung injury in mice in vivo, as well as myofibroblast activation in vitro. CONCLUSIONS: These findings suggest that Fstl1 plays an important role in lung fibrosis and may offer a potential approach to attenuate RIPF in radiation therapy of patients with thoracic cancer.


Assuntos
Proteínas Relacionadas à Folistatina/fisiologia , Fibrose Pulmonar/prevenção & controle , Pneumonite por Radiação/prevenção & controle , Animais , Diferenciação Celular/efeitos da radiação , Proteínas Relacionadas à Folistatina/sangue , Proteínas Relacionadas à Folistatina/genética , Deleção de Genes , Humanos , Macaca mulatta , Masculino , Camundongos , Miofibroblastos/efeitos da radiação , Fibrose Pulmonar/etiologia
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