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1.
Int Immunopharmacol ; 109: 108880, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35689956

RESUMO

OBJECTIVE: This study investigated the mechanism by which microRNA-129-5p (miR-129-5p) in macrophages affects pulmonary fibrosis in rats by regulating the expression of the signal transducer and activator of transcription 1 (STAT1) gene. METHODS: After the establishment of a pulmonary fibrosis rat model, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to detect the expression of miR-129-5p in the sham group and model group. The binding sites between miR-129-5p and STAT1 were predicted online and verified by using a dual luciferase reporter system. qRT-PCR and Western blot analyses were used to test the effect of miR-129-5p on STAT1 gene expression. M2 macrophages were isolated and induced, and exosomes were extracted. Cell proliferation was detected by EdU. Furthermore, qRT-PCR was performed to detect the expression of STAT1, collagen type I A2 (COL1A2), collagen type III A1 (COL3A1), fibronectin, and α-SMA in cells and tissues followed by the detection of CD9, CD63, CD81, CD31 and STAT1 protein expression using a Western blot analysis. The pulmonary fibrosis area was detected by Masson staining followed by the immunohistochemical detection of α-smooth muscle actin (α-SMA) and type I collagen (COL-I) expression in pulmonary fibroblasts. RESULTS: Compared with the sham group, the expression level of miR-129-5p in the model group was significantly increased (P < 0.05). miR-129-5p was observed to negatively regulate the expression of STAT1 (P < 0.05). The in vitro cell transfection experiments showed that after inhibiting the expression of miR-129-5p, the expression of STAT1 was increased, and the proliferation of fibroblasts and pulmonary fibrosis were inhibited (all P < 0.05). Furthermore, compared with the fibroblasts without coculture, the proliferation of the fibroblasts cocultured with M2 macrophage-secreted exosomes was clearly increased, and the expression levels of COL1A2, COL3A1, fibronectin and α-SMA were significantly increased (all P < 0.05). Compared with the mimic NC-exo group, the miR-129-5p-exo group had significantly increased proliferation of fibroblasts, decreased expression of STAT1, and significantly increased expression of COL1A2, COL3A1, fibronectin and α-SMA, and M2 macrophage-secreted exosomes could carry miR-129-5p to fibroblasts. Furthermore, the in vivo experiment confirmed that the exosomes of M2 macrophages could carry miR-129-5p, which could regulate M2 macrophages with pulmonary fibrosis in vivo. CONCLUSION: M2 macrophages can carry miR-129-5p to pulmonary interstitial fibroblasts and inhibit STAT1 gene expression, which may lead to the proliferation of fibroblasts and promote pulmonary fibrosis. The downregulation of miR-129-5p can significantly promote STAT1 gene expression in macrophages to inhibit pulmonary fibrosis in rats.


Assuntos
MicroRNAs , Fibrose Pulmonar , Animais , Proliferação de Células/genética , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Expressão Gênica , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fibrose Pulmonar/metabolismo , Ratos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo
2.
Pak J Pharm Sci ; 35(2): 539-546, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35642410

RESUMO

Dexamethasone is a glucocorticoid that is used for the treatment of interstitial pneumonia and pulmonary fibrosis as it possesses anti-inflammatory and anti-fibrosis properties. In the current study, A549 cells were exposed to paraquat, dexamethasone, or both of them, to investigate the potential effect of dexamethasone against paraquat-triggered poisoning in A549 cells. The inflammatory response was evaluated by measuring tumor necrosis factor-α, interleukin-1ß, and interleukin-6 while the degree of fibrosis was assessed by detecting collagen I and fibronectin using enzyme-linked immunosorbent assay. Western blotting was used to assess the protein expression of apoptotic proteins as well as transforming growth factor-ß1, Smad 3 and phospho-Smad 3. DNA ladder assay was performed to estimate DNA damage in different groups of the alveolar epithelial cells. Dexamethasone protected against paraquat-induced inflammatory response as shown by the significantly reduced levels of the pro-inflammatory cytokines and it also alleviated paraquat-provoked fibrosis as it substantially diminished collagen I and fibronectin levels. Moreover, dexamethasone remarkably decreased the relative expression levels of transforming growth factor-ß1 and phospho-Smad3 that were upregulated upon PQ treatment. Dexamethasone also protected against paraquat-induced genotoxicity and apoptosis. In conclusion, dexamethasone may protect against paraquat-induced inflammation, fibrosis, genotoxicity, and apoptosis via modulating TGF-ß1/Smad 3 signaling pathway.


Assuntos
Dexametasona , Fibrose Pulmonar , Proteína Smad3 , Fator de Crescimento Transformador beta1 , Células A549 , Apoptose , Colágeno/metabolismo , Dexametasona/farmacologia , Fibronectinas/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Paraquat/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
3.
Life Sci ; 303: 120662, 2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-35636582

RESUMO

AIMS: In pulmonary fibrosis, autophagy handles the maintenance of alveolar epithelial cells, prevents epithelial-mesenchymal transition (EMT), and controls collagen turnover. The mammalian target of rapamycin (mTOR) and its translational-dependent proteins are essential regulators of autophagy. Irbesartan (IRB) has earlier ameliorative effects in experimental pulmonary fibrosis. The current study aimed to explore therapeutic autophagy-modulated pulmonary fibrotic changes by IRB versus rapamycin (RAPA) in bleomycin (BLM)-challenged rats. MATERIALS AND METHODS: A single intratracheal BLM dose at day (0), IRB in different doses (10, 20, and 40 mg/kg) or RAPA (2.5 mg/kg) was given daily for 14 continuous days. KEY FINDINGS: IRB significantly diminished the fibrotic lung scores. Pulmonary levels of transforming growth factor (TGF)-ß1 and hydroxyproline exhibited marked attenuation in IRB (40 mg/kg)-treated rats compared to other treated groups. IRB (40 mg/kg) was not significantly different from RAPA. It downregulated the fibrotic lung phosphorylated mammalian target of rapamycin (p-mTOR) levels and augmented lung Unc-51-like autophagy activating kinase 1 (ULK1), LC3-I and LC3-II more than IRB (10 and 20 mg/kg)-treated fibrotic groups. SIGNIFICANCE: Autophagic effects via the mTOR signalling pathway may play a role in IRB's antifibrotic effects. Consideration of IRB as a therapeutic antifibrotic agent in pulmonary fibrosis needs further experimental and clinical long-term validation, especially in comorbid with primary hypertension, heart failure, and diabetic renal insults.


Assuntos
Fibrose Pulmonar , Animais , Autofagia , Bleomicina/toxicidade , Transição Epitelial-Mesenquimal , Irbesartana/farmacologia , Irbesartana/uso terapêutico , Mamíferos/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Ratos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
5.
Cells ; 11(9)2022 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-35563778

RESUMO

Fibrosis is an energy-intensive process requiring the activation of fibroblasts to myofibroblasts, resulting in the increased synthesis of extracellular matrix proteins. Little is known about the transcriptional control of energy metabolism in cardiac fibroblast activation, but glutaminolysis has been implicated in liver and lung fibrosis. Here we explored how pro-fibrotic TGFß and its effector scleraxis, which drive cardiac fibroblast activation, regulate genes involved in glutaminolysis, particularly the rate-limiting enzyme glutaminase (GLS1). The GLS1 inhibitor CB-839 attenuated TGFß-induced fibroblast activation. Cardiac fibroblast activation to myofibroblasts by scleraxis overexpression increased glutaminolysis gene expression, including GLS1, while cardiac fibroblasts from scleraxis-null mice showed reduced expression. TGFß induced GLS1 expression and increased intracellular glutamine and glutamate levels, indicative of increased glutaminolysis, but in scleraxis knockout cells, these measures were attenuated, and the response to TGFß was lost. The knockdown of scleraxis in activated cardiac fibroblasts reduced GLS1 expression by 75%. Scleraxis transactivated the human GLS1 promoter in luciferase reporter assays, and this effect was dependent on a key scleraxis-binding E-box motif. These results implicate scleraxis-mediated GLS1 expression as a key regulator of glutaminolysis in cardiac fibroblast activation, and blocking scleraxis in this process may provide a means of starving fibroblasts of the energy required for fibrosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Glutaminase , Fibrose Pulmonar , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fibroblastos/metabolismo , Glutaminase/genética , Camundongos , Miofibroblastos/metabolismo , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta/metabolismo
6.
Respir Res ; 23(1): 131, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610699

RESUMO

BACKGROUND: Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis. METHODS: Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated. RESULTS: Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice. CONCLUSIONS: In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.


Assuntos
Asma , Hipersensibilidade , Doença Pulmonar Obstrutiva Crônica , Fibrose Pulmonar , Alérgenos , Animais , Asma/metabolismo , Biomarcadores/metabolismo , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Fibrose , Humanos , Hipersensibilidade/metabolismo , Leptina , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fibrose Pulmonar/metabolismo , Pyroglyphidae , RNA Mensageiro/metabolismo
7.
J Cell Mol Med ; 26(11): 3269-3280, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35510614

RESUMO

Pulmonary fibrosis (PF) is a progressive interstitial lung disease with limited treatment options. The incidence and prevalence of PF is increasing with age, cell senescence has been proposed as a pathogenic driver, the clearance of senescent cells could improve lung function in PF. FOXO4-D-Retro-Inverso (FOXO4-DRI), a synthesis peptide, has been reported to selectively kill senescent cells in aged mice. However, it remains unknown if FOXO4-DRI could clear senescent cells in PF and reverse this disease. In this study, we explored the effect of FOXO4-DRI on bleomycin (BLM)-induced PF mouse model. We found that similar as the approved medication Pirfenidone, FOXO4-DRI decreased senescent cells, downregulated the expression of senescence-associated secretory phenotype (SASP) and attenuated BLM-induced morphological changes and collagen deposition. Furthermore, FOXO4-DRI could increase the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts, and decrease the myofibroblasts in bleomycin (BLM)-induced PF mouse model. Compared with mouse and human lung fibroblast cell lines, FOXO4-DRI is inclined to kill TGF-ß-induced myofibroblast in vitro. The inhibited effect of FOXO4-DRI on myofibroblast lead to a downregulation of extracellular matrix (ECM) receptor interaction pathway in BLM-induced PF. Above all, FOXO4-DRI ameliorates BLM-induced PF in mouse and may be served as a viable therapeutic option for PF.


Assuntos
Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Proteínas de Ciclo Celular/metabolismo , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo
8.
Exp Mol Med ; 54(5): 662-672, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35624153

RESUMO

Excessive oxidative stress causes lysosomal membrane permeabilization (LMP), which leads to cell death. Vacuolar ATPase (V-ATPase) is the enzyme responsible for pumping H+ into the cytosol and thus maintaining intracellular pH. Previously, we reported that V-ATPase B2 subunit expression is upregulated in the TiO2-exposed lung epithelium. We investigated the role of the lysosomal V-ATPase B2 subunit in oxidative stress-induced alveolar epithelial cell death and in an experimental lung injury/fibrosis model. Overexpression of V-ATPase B2 increased lysosomal pH and lysosomal activities in the cells. In the presence of H2O2, overexpression of V-ATPase B2 increased survival, and silencing of V-ATPase B2 dramatically increased cell death. Overexpression of V-ATPase B2 diminished H2O2-triggered LMP, as evidenced by a reduction in acridine orange staining and leakage of cathepsin D from the lysosome to the cytoplasm. In addition, V-ATPase B2-overexpressing macrophages exhibited significantly enhanced uptake and degradation of collagen. V-ATPase B2-overexpressing transgenic mice showed significant inhibition of the bleomycin-induced increases in lung inflammation and fibrosis. We conclude that V-ATPase B2 is critical for maintaining lysosomal activities against excessive oxidative stress by stabilizing LMP. Our findings reveal a previously unknown role of this V-ATPase subunit in a lung injury and fibrosis model.


Assuntos
Lesão Pulmonar , Fibrose Pulmonar , ATPases Vacuolares Próton-Translocadoras/metabolismo , Animais , Colágeno/metabolismo , Fibrose , Peróxido de Hidrogênio/metabolismo , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Lisossomos/metabolismo , Camundongos , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética
9.
Biomed Mater ; 17(4)2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35617946

RESUMO

Associated with a high mortality rate, pulmonary fibrosis (PF) is the end stage of several interstitial lung diseases. Although many factors are linked to PF progression, initiation of the fibrotic process remains to be studied. Current research focused on generating new strategies to gain a better understanding of the underlying disease mechanism as the animal models remain insufficient to reflect human physiology. Herein, to account complex cellular interactions within the fibrotic tissue, a multicellular spheroid model where human bronchial epithelial cells incorporated with human lung fibroblasts was generated and treated with bleomycin (BLM) to emulate drug-induced PF. Recapitulating the epithelial-interstitial microenvironment, the findings successfully reflected the PF disease, where excessive alpha smooth muscle actin and collagen type I secretion were noted along with the morphological changes in response to BLM. Moreover, increased levels of fibrotic linked COL13A1, MMP2, WNT3 and decreased expression level of CDH1 provide evidence for the model reliability on fibrosis modelling. Subsequent administration of the Food and Drug Administration approved nintedanib and pirfenidone anti-fibrotic drugs proved the drug-responsiveness of the model.


Assuntos
Fibrose Pulmonar , Animais , Bleomicina/metabolismo , Bleomicina/toxicidade , Modelos Animais de Doenças , Humanos , Pulmão/metabolismo , Pulmão/patologia , Preparações Farmacêuticas/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Reprodutibilidade dos Testes , Esferoides Celulares
10.
Int J Mol Sci ; 23(9)2022 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-35563311

RESUMO

In our previous work, we evaluated the therapeutic effects of 1α,25-Dihydroxyvitamin D3, the biologically active form of vitamin D, in the context of bleomycin-induced lung fibrosis. Contrary to the expected, vitamin D supplementation increased the DNA damage expression and cellular senescence in alveolar epithelial type II cells and aggravated the overall lung pathology induced in mice by bleomycin. These effects were probably due to an alteration in the cellular DNA double-strand breaks' repair capability. In the present work, we have evaluated the effects of two hypocalcemic vitamin D analogs (calcipotriol and paricalcitol) in the expression of DNA damage in the context of minilungs derived from human embryonic stem cells and in the cell line A549.


Assuntos
Células-Tronco Embrionárias Humanas , Fibrose Pulmonar , Animais , Bleomicina/efeitos adversos , Dano ao DNA , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Vitamina D/farmacologia , Vitamina D/uso terapêutico
11.
Int J Mol Sci ; 23(10)2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35628193

RESUMO

Pulmonary fibrosis therapy is limited by the unclear mechanism of its pathogenesis. C57BL/6 mice were used to construct the pulmonary fibrosis model in this study. The results showed that Men1, which encodes menin protein, was significantly downregulated in bleomycin (BLM)-induced pulmonary fibrosis. Mice were made to overexpress or had Men1 knockdown with adeno-associated virus (AAV) infection and then induced with pulmonary fibrosis. BLM-induced pulmonary fibrosis was attenuated by Men1 overexpression and exacerbated by Men1 knockdown. Further analysis revealed the distinct roles of Men1 in fibroblasts and macrophages. Men1 inhibited fibroblast activation and extracellular matrix (ECM) protein expression while promoting macrophages to be profibrotic (M2) phenotype and enhancing their migration. Accordingly, pyroptosis was potentiated by Men1 in mouse peritoneal macrophages (PMCs) and lung tissues upon BLM stimulation. Furthermore, the expression of profibrotic factor OPN was positively regulated by menin in Raw264.7 cells and lung tissues by binding to the OPN promoter region. Taken together, although Men1 showed antifibrotic properties in BLM-induced pulmonary fibrosis mice, conflictive roles of Men1 were displayed in fibroblasts and macrophages. The profibrotic role of Men1 in macrophages may occur via the regulation of macrophage pyroptosis and OPN expression. This study extends the current pathogenic understanding of pulmonary fibrosis.


Assuntos
Neoplasia Endócrina Múltipla Tipo 1 , Proteínas Proto-Oncogênicas , Fibrose Pulmonar , Animais , Bleomicina/toxicidade , Fibroblastos/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasia Endócrina Múltipla Tipo 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo
12.
Am J Chin Med ; 50(4): 1063-1094, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35475972

RESUMO

Pulmonary fibrosis (PF) is a highly confounding and fatal pathological process with finite treatment options. Multiple factors such as oxidative and immune/inflammation involve key pathological processes in chronic lung disease, and their intimate interactions mediate chronic lung damage, denudation of the alveolar epithelium, hyperproliferation of type II alveolar epithelial cells (AECIIs), proliferation and differentiation of fibroblasts, and the permeability of microvessels. We reviewed the classic mechanism of PF and highlighted a few emerging mechanisms for studying complex networks in lung disease pathology. Polyphenols, as a multi-target drug, has excellent potential in the treatment of pulmonary fibrosis. We then reviewed recent advances in discovering phenolic compounds from fruits, tea, and medical herbs with the bioactivities of simultaneously regulating multiple factors (e.g., oxidative stress, inflammation, autophagy, apoptosis, pyroptosis) for minimizing pulmonary fibrosis injury. These compounds include resveratrol, curcumin, salvianolic acid B, epigallocatechin-3-gallate, gallic acid, corilagin. Each phenolic compound can exert its anti-PF effect through various mechanisms, and the signaling pathways involved in different phenolic compounds are not the same. This review summarized the available evidence on phenolic compounds' effectiveness in pulmonary diseases and explored the molecular mechanisms and therapeutic targets of phenolic compounds from Chinese herbal medicine with the properties of inhibition of ongoing fibrogenesis and resolution of existing fibrosis.


Assuntos
Medicamentos de Ervas Chinesas , Fibrose Pulmonar , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Fibroblastos/metabolismo , Fibrose , Humanos , Inflamação/tratamento farmacológico , Fenóis/farmacologia , Polifenóis/metabolismo , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo
13.
BMC Pharmacol Toxicol ; 23(1): 21, 2022 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-35387687

RESUMO

BACKGROUND: The objective of this article is to observe the expression of Wnt-induced secreted proteins-1 (WISP1) in paraquat (PQ)-induced pulmonary fibrosis (PF) to explore the role of WISP1. METHODS: Healthy individuals were included in the control group. Patients who had acute lung injury or PF were included in the PF group. Venous blood samples were collected from the patients on days 1 and 3 following PQ poisoning to detect the expression levels of the WISP1 gene and protein concentration. Any changes in the patients' blood gas analysis index were reviewed. In addition, chest computed tomography (CT) and x-ray images were observed to evaluate the relationship between WISP1 expression and disease severity. RESULTS: The expression of the WISP1 gene and the serum WISP1 protein concentration were higher in patients with PQ poisoning combined with PF than in patients without PF (P < 0.01). Serum PQ concentration was positively correlated with WISP1 gene expression (r = 0.621, P < 0.01), and serum WISP1 protein concentration (r = 0.596, P < 0.01) was considered a risk factor [odds ratio (OR) = 4.356, P < 0.05] for PQ-induced PF. Concurrently, the results of the adjusted and non-adjusted OR value for WISP1 gene expression and WISP1 protein concentration on day 1 was, respectively, as follows: OR = 12.797, 95% confidence interval (CI) (2.478-66.076), P = 0.002, OR' = 11.353, P = 0.005; and OR = 1.545, 95% CI (1.197-1.995), P = 0.001, OR' = 1.487, P = 0.003. The CT scan of a 20-year-old male with PQ-induced PF (20 ml) was observed, and it showed a typical hyaline-like lesion in the lungs on day 22 after poisoning; on day 33 after poisoning, the lungs showed localised consolidation combined with air bronchography. CONCLUSION: The expression of WISP1 was higher in the patients with PQ-induced PF compared with the patients without PF. Accordingly, WISP1 plays an important role in PQ-induced PF.


Assuntos
Paraquat , Fibrose Pulmonar , Adulto , Humanos , Pulmão/metabolismo , Masculino , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/metabolismo , Tomografia Computadorizada por Raios X , Adulto Jovem
14.
BMC Pulm Med ; 22(1): 140, 2022 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-35410283

RESUMO

BACKGROUND: Pulmonary fibrosis is a fatal lung disease with complex pathogenesis and limited effective therapies. Salt-inducible kinase 2 (SIK2) is a kinase that phosphorylates CRTCs and regulates many physiological processes. However, the role of SIK2 on pulmonary fibrosis remains unclear, and whether SIK2 inhibitor can attenuate pulmonary fibrosis is unknown. METHOD: We subjected human fetal lung fibroblasts (HFLs) to transforming growth factor-ß1 (5 ng/mL) for 12 h, and examined the expression of SIK2, CRTCs and pCRTCs in fibroblasts by western-blot. To address the roles of SIK2 and CRTCs involved in the progression of pulmonary fibrosis, HFLs were treated with a small-molecule inhibitor ARN-3236 or by siRNA-mediated knockdown of SIK2 expression. Pulmonary fibrosis model was established with mice by exposing to bleomycin, and assessed by H&E and Masson's trichrome staining. COL1A and α-SMA distributions were detected in lung tissues by immunohistochemical staining. RESULTS: We discovered that SIK2 and phosphorylated-CRTC2 were expressed at a low basal level in normal lung tissues and quiescent fibroblasts, but increased in fibrotic lung tissues and activated fibroblasts. Inhibition of SIK2 by ARN-3236 prevented the fibroblasts differentiation and extracellular matrix expression in HFLs and attenuated bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inactivation of SIK2 resulted in the dephosphorylation and nuclear translocation of CRTC2. Within the nucleus, CRTC2 binds to CREB, promoting CREB-dependent anti-fibrotic actions. CONCLUSION: In conclusion, our results elucidated a previously unexplored role of SIK2 in pulmonary fibrosis, and identified SIK2 as a new target for anti-fibrosis medicines.


Assuntos
Bleomicina , Fibrose Pulmonar , Animais , Bleomicina/toxicidade , Fibroblastos/metabolismo , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
15.
J Exp Clin Cancer Res ; 41(1): 128, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35392967

RESUMO

BACKGROUND: Radiation-induced lung fibrosis (RILF) is a common complication of thoracic radiotherapy. Alveolar epithelial cells play a crucial role in lung fibrosis via epithelial-mesenchymal transition (EMT). Exosomes derived from mesenchymal stem cells own the beneficial properties to repair and regeneration of damaged tissues, however the underlying mechanisms remain poorly understood. METHODS: Mouse mesenchymal stem cells-derived exosomes (mMSCs-Exo) were isolated by differential centrifugation, and their protective effects were assessed in vivo and in vitro, respectively. EMT-associated proteins were measured via western blot assay and/or immunofluorescence staining. The miRNA expression was measured by microarray assay and qPCR. Furthermore, bioinformatics prediction with KEGG analysis, luciferase assay, and rescue experiments were performed to explore the molecular mechanism underlying miR-466f-3p. RESULTS: mMSCs-Exos were efficiently isolated ranging from 90-150 nm with high expression of exosomal markers (CD63, TSG101, and CD9). mMSCs-Exos administration efficiently relieved radiation-induced lung injury with less collagen deposition and lower levels of IL-1ß and IL-6. Meanwhile, in vitro results showed mMSCs-Exos treatment obviously reversed EMT process induced by radiation. Among enriched miRNA cargo in exosomes, miR-466f-3p was primarily responsible for the protective effects via inhibition of AKT/GSK3ß pathway. Our mechanistic study further demonstrated that c-MET was the direct target of miR-466f-3p, whose restoration partially abrogated mMSCs-Exo-mediated inhibition in both EMT process and AKT/GSK3ß signaling activity induced by radiation. CONCLUSIONS: Our findings indicated that exosomal miR-466f-3p derived from mMSCs may possess anti-fibrotic properties and prevent radiation-induced EMT through inhibition of AKT/GSK3ß via c-MET, providing a promising therapeutic modality for radiation-induced lung fibrosis.


Assuntos
Exossomos , Lesão Pulmonar , Células-Tronco Mesenquimais , MicroRNAs , Fibrose Pulmonar , Animais , Transição Epitelial-Mesenquimal/fisiologia , Exossomos/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Lesão Pulmonar/genética , Lesão Pulmonar/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fibrose Pulmonar/metabolismo
16.
Eur J Pharmacol ; 923: 174931, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35398392

RESUMO

CONTEXT: Oridonin (Ori) possesses anti-inflammatory, antioxidant and antitumor properties. However, the effects of Ori on Lipopolysaccharide (LPS)-induced early pulmonary fibrosis remain unclear. OBJECTIVE: We evaluated the protective effects of Ori on the mice model of pulmonary fibrosis. MATERIALS AND METHODS: The BALB/C mice were given LPS (1 mg/kg) or Ori (20 mg/kg) according to experimental grouping. Then the left lung tissues were used for HE, immunohistochemical and Masson staining, and the right lung tissues were used for hydroxyproline measurement and western blot experiments. Bronchoalveolar lavage fluid was collected for Giemsa staining. RESULTS: The high levels of hydroxyproline induced by LPS were reduced by Ori treatment. Immunohistochemical staining and western blot analysis showed that Ori inhibited the increased levels of fibrosis-related proteins (α-smooth muscle actin, transforming growth factor-ß, Collagen Ⅰ and phosphorylated-smad). Additionally, Ori treatment increased E-cadherin levels and decreased in Snail and Slug levels. Besides, Ori could suppress LPS-induced the infiltration of neutrophils and activation of the NLRP3 inflammasome. In addition, LPS caused the upregulation of NADPH oxidase 4 and exacerbated lung fibrosis. As the activator of NF-E2 related factor-2, Ori exerted protective effects in this animal model. Moreover, Ori reversed the LPS-triggered increases in Beclin-1, P62/sequestosome 1, autophagy related 3 and LC3. CONCLUSIONS: These findings suggested that Ori protected against LPS-induced early pulmonary fibrosis by inhibiting NLRP3-dependent inflammation, NADPH oxidase 4-dependent oxidative stress, the impaired autophagy and epithelial mesenchymal transformation.


Assuntos
Fibrose Pulmonar , Animais , Autofagia , Modelos Animais de Doenças , Diterpenos do Tipo Caurano , Hidroxiprolina/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , NADPH Oxidase 4/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo
17.
Bioengineered ; 13(4): 10098-10110, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35435119

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a common pulmonary interstitial disease with a high mortality rate. Adiponectin (APN) is reportedly an effective therapy for fibrosis-related diseases. This study aimed to investigate the potential effects of APN on IPF. Male BALB/c mice were injected with bleomycin (BLM) and treated with different doses of APN (0.1, 0.25, and 0.5 mg/kg). The body weights of the mice were recorded. Immunohistochemical, hematoxylin and eosin, and Masson staining were performed to evaluate pulmonary histopathological changes. Enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to assess tissue inflammation. The human lung fibroblasts HELF were stimulated with TGF-ß1 and treated with different doses of APN (2.5, 5, and 10 µg/ml). Cell proliferation, inflammation, and fibrosis were determined by MTT assay, EdU assay, colony formation assay, ELISA, and western blotting. APN significantly attenuated BLM-induced body weight loss, alveolar destruction, and collagen fiber accumulation in mice (p < 0.05). APN decreased the expression of α-SMA and collagen I and reduced the concentration of TNF-α, IL-6, IL-1ß, and IL-18 in lung tissues (p < 0.05). In TGF-ß1-treated HELF cells, cell proliferation and colony formation were inhibited by APN (p < 0.05). Additionally, the expression of α-SMA, collagen I, and pro-inflammatory cytokines were suppressed by APN (p < 0.05). APN inhibited the phosphorylation of IκB and nuclear translocation of p65. In conclusion, these findings suggest that APN is an effective agent for controlling IPF progression. The antifibrotic effects of APN might be mediated via inhibiting the NF-κB signaling pathway.


Assuntos
Fibrose Pulmonar , Adiponectina/metabolismo , Adiponectina/farmacologia , Adiponectina/uso terapêutico , Animais , Bleomicina/toxicidade , Colágeno/metabolismo , Fibroblastos/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Masculino , Camundongos , NF-kappa B/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
PLoS One ; 17(4): e0266163, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35377906

RESUMO

OBJECTIVE AND DESIGN: We examined the role of eCIRP in the pathogenesis of bleomycin-induced pulmonary fibrosis (PF). MATERIAL AND METHODS: Publicly available gene expression omnibus datasets were analyzed for the expression of CIRP in lung samples from patients with PF. Wild type (WT) or CIRP-/- mice received daily injections of 10 µg/g bleomycin for 10 days. A subset of bleomycin-injected WT mice was treated with the eCIRP antagonist C23 (8 µg/g/day) from day 10 to day 19. At three weeks, transthoracic echocardiography was performed to measure the degree of pulmonary hypertension, and lung tissues were collected and analyzed for markers of fibrosis. RESULTS: Analysis of the mRNA data of human lung samples showed a significant positive correlation between CIRP and α-smooth muscle actin (α-SMA), an important marker of fibrosis. Moreover, the expression of CIRP was higher in patients with acute exacerbation of PF than in patients with stable PF. CIRP-/- mice showed attenuated induction of α-SMA and collagens (Col1a1, Col3a1), reduced hydroxyproline content, decreased histological fibrosis scores, and improved pulmonary hypertension as compared to WT mice. WT mice treated with C23 also had significant attenuation of the above endpoint measure. CONCLUSIONS: Our study demonstrates that eCIRP plays a key role in promoting the development of PF, and blocking eCIRP with C23 can significantly attenuate this process.


Assuntos
Hipertensão Pulmonar , Fibrose Pulmonar , Animais , Bleomicina/farmacologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/metabolismo , Pulmão/patologia , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo
19.
Burns ; 48(4): 880-895, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35410697

RESUMO

BACKGROUND: Tranilast (N-[3',4'-dimethoxycinnamoyl]-anthranilic acid) is an analog of a tryptophan metabolite. It was identified with anti-inflammatory and antifibrotic activities, and used in the treatment of a variety of diseases, such as anti - allergy, bronchial asthma, and hypertrophic scars. As a drug with few adverse reactions, tranilast has attracted great attention, but its application is limited due to the uncertainty of dosages and mechanisms. In this study, the protection effects of different doses of tranilast on smoke inhalation mediated lung injury on rats, and on the damage of three kinds of lung cells in vitro were investigated. METHOD: In vivo, Sprague-Dawley rats were randomly divided into sham group, smoke group (rats were exposed to pine sawdust smoke three times, each time for 5 min), different doses of tranilast treatment group (doses were 100 mg/kg, 200 mg/kg and 300 mg/kg, ip.) and placebo group. After 1, 3 and 7 days, pulmonary function, pathologic injury by HE staining, cytokines and oxidative stress level by kits were determined. At 7days, lung fibrosis was assessed by Masson's trichrome staining and the level of hydroxyproline (HYP). In vitro, three kinds of lung cells from normal rats were isolated: type II alveolar epithelial cells (AT-II), pulmonary microvascular endothelial cells (PMVECs) and pulmonary fibroblasts (PFs). To investigate the potential effects of tranilast on cell proliferation, cell cycle and cytokine production of three kinds of lung cells exposed to smoke. RESULTS: Compared with smoke group and placebo group, tranilast treatment significantly reduced histopathological changes (such as pulmonary hemorrhage, edema and inflammatory cell infiltration, etc.), significantly reduced histopathological score (p < 0.05), increased arterial oxygen partial pressure, and decreased the levels of IL-1ß, TNF-α, TGF-ß1 (p < 0.05), oxidative stress and the expression of nuclear transcription factor κB (NF-κB) smoke exposed rats (p < 0.01). In particular, the effect of 200 mg/kg dose was more prominent. In vitro, smoke induced AT-II and PMVECs apoptosis, improved PFs proliferation (p < 0.01), activity of SOD and decreased the content of MDA (p < 0.01). However, tranilast seems to be turning this trend well. The inflammatory factor IL-11ß, TNF-α and TGF-ß1, and the expression of NF-κB were significantly lower in the tranilast treatment than in the smoke group (p < 0.01). CONCLUSION: This study indicates that tranilast had a protective effect on acute respiratory distress syndrome and early pulmonary fibrosis of rats in vivo. In addition, tranilast promotes proliferation of AT-II and PMVECs but inhibits PFs proliferation, down-regulates secretion of inflammatory cytokines and alleviates oxidative stress of AT-II, PMVECs and PFs after smoke stimuli in vitro.


Assuntos
Queimaduras , Fibrose Pulmonar , Síndrome do Desconforto Respiratório , Lesão por Inalação de Fumaça , Animais , Citocinas/metabolismo , Células Endoteliais/metabolismo , Humanos , Pulmão/metabolismo , NF-kappa B/metabolismo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa , ortoaminobenzoatos
20.
Sci Total Environ ; 831: 154974, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35378184

RESUMO

Airborne fine particulate matter (PM2.5) is considered to be a risk factor for lung fibrosis, and therefore, it has attracted public attention due to its various physicochemical features and its adverse effects on health. However, little remains to be known regarding the mechanism of PM2.5-induced pulmonary fibrosis. The lung microbiota may be a potential factor involved in the adverse outcomes of pulmonary fibrosis. Meanwhile, miRNAs are thought to be key regulators that participate in the complex interplay between the host and the microbiota. Hence, to investigate the potential mechanisms of pulmonary fibrosis, and to explore the impact of PM2.5-induced alterations in miRNAs and the lung microbiota and possible interaction patterns in mice models, we took advantage of 16S rDNA gene sequencing, miRNAs sequencing (miRNAs-Seq), and mining of public databases profiling. The results of 16S rDNA analysis showed that PM2.5 interfered with the microbial community composition, resulting in Proteobacteria becoming an additional dominant phylum. In addition, differentially expressed miRNAs were enriched in HIF-1 signaling, the IL-17 signaling, as well as Th17 cell differentiation pathways, which are closely related to microbial functional pathways. Significantly, a target miRNA, miR-149-5p, may be a key factor triggering the MAPK signal pathway related to pulmonary fibrosis and disturbing the homeostasis of lung bacterial flora. These results indicate that PM2.5 may lead to interaction between lung microbiota dysbiosis and an imbalance of miRNA levels to form a vicious cycle that promotes lung fibrogenesis. The current study provides new insights into the progression of pulmonary fibrosis.


Assuntos
MicroRNAs , Microbiota , Fibrose Pulmonar , Animais , DNA Ribossômico , Pulmão/patologia , Camundongos , MicroRNAs/genética , Material Particulado/metabolismo , Material Particulado/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Transcriptoma
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