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1.
Korean J Radiol ; 21(6): 746-755, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32410413

RESUMO

OBJECTIVE: To identify predictors of pulmonary fibrosis development by combining follow-up thin-section CT findings and clinical features in patients discharged after treatment for COVID-19. MATERIALS AND METHODS: This retrospective study involved 32 confirmed COVID-19 patients who were divided into two groups according to the evidence of fibrosis on their latest follow-up CT imaging. Clinical data and CT imaging features of all the patients in different stages were collected and analyzed for comparison. RESULTS: The latest follow-up CT imaging showed fibrosis in 14 patients (male, 12; female, 2) and no fibrosis in 18 patients (male, 10; female, 8). Compared with the non-fibrosis group, the fibrosis group was older (median age: 54.0 years vs. 37.0 years, p = 0.008), and the median levels of C-reactive protein (53.4 mg/L vs. 10.0 mg/L, p = 0.002) and interleukin-6 (79.7 pg/L vs. 11.2 pg/L, p = 0.04) were also higher. The fibrosis group had a longer-term of hospitalization (19.5 days vs. 10.0 days, p = 0.001), pulsed steroid therapy (11.0 days vs. 5.0 days, p < 0.001), and antiviral therapy (12.0 days vs. 6.5 days, p = 0.012). More patients on the worst-state CT scan had an irregular interface (59.4% vs. 34.4%, p = 0.045) and a parenchymal band (71.9% vs. 28.1%, p < 0.001). On initial CT imaging, the irregular interface (57.1%) and parenchymal band (50.0%) were more common in the fibrosis group. On the worst-state CT imaging, interstitial thickening (78.6%), air bronchogram (57.1%), irregular interface (85.7%), coarse reticular pattern (28.6%), parenchymal band (92.9%), and pleural effusion (42.9%) were more common in the fibrosis group. CONCLUSION: Fibrosis was more likely to develop in patients with severe clinical conditions, especially in patients with high inflammatory indicators. Interstitial thickening, irregular interface, coarse reticular pattern, and parenchymal band manifested in the process of the disease may be predictors of pulmonary fibrosis. Irregular interface and parenchymal band could predict the formation of pulmonary fibrosis early.


Assuntos
Infecções por Coronavirus/diagnóstico por imagem , Pneumonia Viral/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/virologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Masculino , Microtomia/métodos , Pessoa de Meia-Idade , Pandemias , Alta do Paciente , Derrame Pleural/patologia , Derrame Pleural/virologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Valor Preditivo dos Testes , Fibrose Pulmonar/patologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
3.
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
4.
Zhonghua Yu Fang Yi Xue Za Zhi ; 54(2): 198-202, 2020 Feb 06.
Artigo em Chinês | MEDLINE | ID: mdl-32074710

RESUMO

Objective: To explore the lung damage caused by repeated inhalation of polyhexamethyleneguanidine (PHMG) disinfectant aerosol and the corresponding toxicological characteristics. Methods: Thirty four-week-old mice of C57BL/6N strain were randomly divided into three groups, the control group, low-dose group, and high-dose group. Each group had 5 male mice and 5 female mice. Lab II-level purified water was used in the control group. The PHMG disinfectant aerosol was generated by using the ultrasonic atomization of the aqueous solution containing PHMG. The PHMG concentrations in the low-and high-dose groups were 0.1 mg/ml (0.01%) and 1 mg/ml (0.1%), respectively. The concentration of PHMG in the post-chemical exposure room was 1.03 mg/m(3) and 9.09 mg/m(3) according to the air sampler analysis. The experimental mice were exposed to the PHMG in dynamic respiratory exposure mode for 4 hours every day in 21 days. After 21-day exposure, bronchia alveolus lung fluids (BALFs) were used to evaluate the inflammatory cells in the lungs, and pathological evaluation, special staining and immunohistochemical methods were further performed to evaluate the key indicators of pulmonary fibrosis. Results: Compared to the control group, the body weight of mice in the high-dose group was significantly decreased (P<0.05), while that of mice in the low-dose group did not significantly differ (P>0.05). The number of inflammatory cells in BALFs of low-dose exposed mice was slightly reduced, and the lung tissue pathology began to show lung damage with early fibrosis symptoms (P<0.05). The pathological examination of mice in the high-dose group showed changes in pulmonary fibrosis. Immunohistochemical staining showed that pulmonary fibrosis marker, α-SMA, was significantly increased in low-dose group and high-dose group (P<0.05). Conclusion: The repeated inhalation of PHMG disinfectant could cause lung damage such as pulmonary fibrosis in mice. It could suggest that special warnings should be given to this common disinfectant and respiratory protection measures should be adopted during industrial production and daily use.


Assuntos
Desinfetantes/toxicidade , Guanidinas/toxicidade , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Administração por Inalação , Animais , Desinfetantes/administração & dosagem , Feminino , Guanidinas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
5.
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
6.
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
7.
Toxicol Lett ; 319: 168-174, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31698045

RESUMO

Sulfur mustard and related vesicants are cytotoxic alkylating agents that cause severe damage to the respiratory tract. Injury is progressive leading, over time, to asthma, bronchitis, bronchiectasis, airway stenosis, and pulmonary fibrosis. As there are no specific therapeutics available for victims of mustard gas poisoning, current clinical treatments mostly provide only symptomatic relief. In this article, the long-term effects of mustards on the respiratory tract are described in humans and experimental animal models in an effort to define cellular and molecular mechanisms contributing to lung injury and disease pathogenesis. A better understanding of mechanisms underlying pulmonary toxicity induced by mustards may help in identifying potential targets for the development of effective clinical therapeutics aimed at mitigating their adverse effects.


Assuntos
Alquilantes/toxicidade , Substâncias para a Guerra Química/toxicidade , Compostos de Mostarda/toxicidade , Doenças Respiratórias/induzido quimicamente , Animais , Humanos , Pulmão/patologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/tratamento farmacológico , Lesão Pulmonar/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/patologia
8.
Am J Physiol Lung Cell Mol Physiol ; 318(2): L376-L385, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851533

RESUMO

The systemic delivery of bleomycin (BLM) to mice through subcutaneously implanted osmotic minipumps may be used to experimentally mimic the typical features of systemic sclerosis and related interstitial lung diseases. The published studies on this model principally have focused on induced dermal modifications, probably because lung lesions are typically mild, subpleurally localized, and difficult to analyze. The use of high BLM doses to increase their severity has been proposed but is ethically questionable because of the compromising of animal welfare. We propose a tailored histomorphometric method suitable to detect and quantify this type of mild lung lesions. Using a two-step automated image analysis, a peripheral region of interest with a depth of 250 µm from the pleural edge was defined on whole slide images, and the fibrotic foci were histomorphometrically characterized. The effects of different BLM doses on lung alterations were evaluated in C57BL/6 mice and 60 U/kg resulted in a fair compromise between fibrotic lesions and animal welfare. This dose was also tested in time course experiments. The analysis revealed a peak of histological fibrotic-like alterations, cytokine expression, metalloprotease, and macrophagic activation between the 21st and 28th day after pump implant. The induced dermal fibrosis was characterized by the progressive loss of the white dermal adipose layer, an increase in dermal thickness, dermal hyperplasia, and more compacted collagen fibers. Despite the trend toward spontaneous resolution, our model allowed a double organ readout of the BLM effect and the identification of a therapeutic window for testing pharmacological compounds without using life-threatening doses.


Assuntos
Bleomicina/administração & dosagem , Bleomicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Bombas de Infusão , Fibrose Pulmonar/tratamento farmacológico , Animais , Derme/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/patologia , Fatores de Tempo
9.
Eur J Med Chem ; 185: 111790, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699535

RESUMO

Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-ß-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-ß-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100 mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-ß/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (F = 39.88%) and suitable eliminated half-life time (T1/2 = 13.09 h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.


Assuntos
Cumarínicos/uso terapêutico , Descoberta de Drogas , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cumarínicos/síntese química , Cumarínicos/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Células RAW 264.7 , Relação Estrutura-Atividade
10.
Proc Natl Acad Sci U S A ; 117(2): 1139-1147, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31879343

RESUMO

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinß1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach.


Assuntos
Proteínas CLOCK/antagonistas & inibidores , Relógios Circadianos/fisiologia , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina/efeitos adversos , Proteínas CLOCK/genética , Proteínas CLOCK/uso terapêutico , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Fibrose Pulmonar Idiopática , Integrinas , Pulmão/patologia , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Knockout , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Proteínas Semelhantes à Proteína de Ligação a TATA-Box/metabolismo , Transcriptoma
11.
Curr Drug Res Rev ; 11(2): 111-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31875783

RESUMO

BACKGROUND: Radiation-induced pneumonitis and fibrosis are the most common side effects of chest radiotherapy. They result from massive and chronic production of Reactive Oxygen Species (ROS), inhibition of antioxidant enzymes as well as the release of several inflammatory mediators. In this study, we aimed to detect the radioprotective effects of metformin (as inhibitor of mitochondrial ROS), resveratrol (as stimulator of antioxidant defense enzymes) and alpha-lipoic acid (as direct antioxidant) for alleviating radiation-induced pneumonitis and fibrosis. METHODS: 80 Male Mice were randomly allotted to eight groups which include G1: control; G2: resveratrol; G3: alpha-lipoic acid; G4: metformin; G5: radiation; G6: radiation plus resveratrol; G7: radiation plus alpha-lipoic acid; G8: radiation plus metformin. Drugs' doses were as follows: 100 mg/kg metformin, 200 mg/kg resveratrol and 200 mg/kg alpha-lipoic acid. Irradiation with a single radiation dose of 18 Gy was performed using a cobalt-60 (60Co) gamma-ray source. After 80 days, all mice were sacrificed and their lung tissues evaluated for morphological changes using histopathological markers. RESULTS: Irradiation led to acute pneumonitis including infiltration of inflammatory cells and damages to alveolar and vascular, as well as mild fibrosis. Metformin, alpha-lipoic acid and resveratrol were able to reduce pneumonitis and overcome radiation-induced fibrosis. CONCLUSION: All agents could protect against radiation-induced lung injury moderately. It is possible that administering higher doses of these drugs over a long period of time could give better radioprotection of the lung.


Assuntos
Antioxidantes/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Pneumonite por Radiação/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Resveratrol/uso terapêutico , Ácido Tióctico/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Pulmão/patologia , Masculino , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos da radiação , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/patologia , Lesões por Radiação/tratamento farmacológico , Lesões por Radiação/patologia , Pneumonite por Radiação/patologia
12.
PLoS Negl Trop Dis ; 13(11): e0007896, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31765381

RESUMO

Ascariasis is considered the most neglected tropical disease, and is a major problem for the public health system. However, idiopathic pulmonary fibrosis (IPF) is a result of chronic extracellular deposition of matrix in the pulmonary parenchyma, and thickening of the alveolar septa, which reduces alveolar gas exchange. Considering the high rates of ascariasis and pulmonary fibrosis, we believe that these two diseases may co-exist and possibly lead to comorbidities. We therefore investigated the mechanisms involved in comorbidity of Ascaris suum (A. suum) infection, which could interfere with the progression of pulmonary fibrosis. In addition, we evaluated whether a previous lung fibrosis could interfere with the pulmonary cycle of A. suum in mice. The most important findings related to comorbidity in which A. suum infection exacerbated pulmonary and liver injury, inflammation and dysfunction, but did not promote excessive fibrosis in mice during the investigated comorbidity period. Interestingly, we found that pulmonary fibrosis did not alter the parasite cycle that transmigrated preferentially through preserved but not fibrotic areas of the lungs. Collectively, our results demonstrate that A. suum infection leads to comorbidity, and contributes to the aggravation of pulmonary dysfunction during pulmonary fibrosis, which also leads to significant liver injury and inflammation, without changing the A. suum cycle in the lungs.


Assuntos
Ascaríase/complicações , Ascaríase/patologia , Hepatopatias/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Animais , Ascaris suum/isolamento & purificação , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Pulmão/parasitologia , Pulmão/patologia , Camundongos Endogâmicos C57BL
13.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 852-857, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694096

RESUMO

Objective: To analyze the clinical,imaging and pathological features of Pleuroparenehymal fibroelastosis (PPFE). Methods: The clinieal data of a patient diagnosed as PPFE admitted in department of Respiratory and Critical Care Medicine,Beijing Hospital in April 2017 were reported and the related literatures were reviewed.With "pleuroparenehymal fibroelastosis" as the search terms, and the search time before October 1st 2017 for Wanfangdata, China National Knowledge Infrastructure(CNKI), and PubMed. Results: The patient was a 46-year-old male presented with cough, shortness of breath after exercise.A CT scan of the chest revealed bilateral, irregular pleural thickening with upper lobe predominance.After 3 years of antituberculosis treatment,the disease progressed. A diagnosis of pleuroparenehymal fibroelastosis (PPFE) was confirmed by CT guided lung biopsy. A total of 132 cases were reported (including 1 case in Chinese). 88 of them were confirmed by pathology with detailed data.Clinical data of 89 reported cases with PPFE including 48 males and 41 females aged 13 to 85 years were enrolled and analyzed in the study.The common symptoms were dyspnea(62%, 55 cases),cough(58%, 52 cases),recurrent respiratory tract infection(17%, 15 cases).The main CT features are reported:pleural thickening(87%,77 cases), recurrent pneumothorax(52%,46 cases), traction bronchiectasis(30%, 27 cases),subpleural comsolidation(20%, 18 cases). All patients were proven PPFE by biopsy.34 cases received corticosteroid, 5 cases received lung transplant operation.40 cases died during the follow-up from 4 month to 84 month. Conclusions: Pleuroparenehymal fibroelastosis is a rare disease.The imaging findings were dominated by both upper lobes. Lung biopsy might be necessary. PPFE is often misdiagnosed as pulmonary tuberculosis/obsolete pulmonary tuberculosis,asbestosis,connective tissues disease and Drug-induced pneumonitis.There was no consensus on the treatment.


Assuntos
Pulmão/diagnóstico por imagem , Tecido Parenquimatoso/patologia , Pleura/patologia , Doenças Pleurais/patologia , Fibrose Pulmonar/patologia , Biópsia , China , Tosse/etiologia , Dispneia/etiologia , Feminino , Humanos , Pulmão/patologia , Pulmão/cirurgia , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Tecido Parenquimatoso/diagnóstico por imagem , Pleura/diagnóstico por imagem , Doenças Pleurais/diagnóstico por imagem , Doenças Pleurais/cirurgia , Fibrose Pulmonar/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
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
15.
Exp Mol Pathol ; 111: 104315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31629729

RESUMO

Caveolin is a structural protein of flask-shaped invaginations of the plasma membrane termed as caveolae and is widely expressed on the endothelial cells, smooth muscle cells and fibroblasts in the different parts of the body including the lung tissues. The expression of caveolin-1 in the lung tissues is important to prevent the fibrogenic actions of TGF-ß1 in lung fibrosis of different etiology including idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease and allergen-induced airway remodeling. Caveolin-1-mediated internalization and degradation of TGF-ß1 receptors may possibly account for the decreased actions of TGF-ß1. Studies have shown that the deficiency of caveolin-1 is very important in inducing lung fibrosis and its upregulation is reported to prevent lung fibrosis. The biological actions of caveolin-1 involve signaling pathways including JNK signaling, IL-4, STAT-3, miR199a-5p, CXCR4+ and CXCL12. The present review discusses the key role of caveolin and associated signaling pathways in the pathogenesis of lung fibrosis of different etiology.


Assuntos
Caveolina 1/fisiologia , Fibrose Pulmonar/etiologia , Remodelação das Vias Aéreas/fisiologia , Animais , Citocinas/metabolismo , Epigênese Genética , Humanos , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fibrose Pulmonar/patologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
16.
Molecules ; 24(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509965

RESUMO

Collagen Tissue Disease-associated Interstitial Lung Fibrosis (CTD-ILDs) and Bronchiolitis Obliterans Syndrome (BOS) represent severe lung fibrogenic disorders, characterized by fibro-proliferation with uncontrolled extracellular matrix deposition. Hyaluronic acid (HA) plays a key role in fibrosis with its specific receptor, CD44, overexpressed by CTD-ILD and BOS cells. The aim is to use HA-liposomes to develop an inhalatory treatment for these diseases. Liposomes with HA of two molecular weights were prepared and characterized. Targeting efficiency was assessed toward CTD-ILD and BOS cells by flow cytometry and confocal microscopy and immune modulation by RT-PCR and ELISA techniques. HA-liposomes were internalized by CTD-ILD and BOS cells expressing CD44, and this effect increased with higher HA MW. In THP-1 cells, HA-liposomes decreased pro-inflammatory cytokines IL-1ß, IL-12, and anti-fibrotic VEGF transcripts but increased TGF-ß mRNA. However, upon analyzing TGF-ß release from healthy donors-derived monocytes, we found liposomes did not alter the release of active pro-fibrotic cytokine. All liposomes induced mild activation of neutrophils regardless of the presence of HA. HA liposomes could be also applied for lung fibrotic diseases, being endowed with low pro-inflammatory activity, and results confirmed that higher MW HA are associated to an increased targeting efficiency for CD44 expressing LFs-derived from BOS and CTD-ILD patients.


Assuntos
Bronquiolite Obliterante/tratamento farmacológico , Ácido Hialurônico/farmacologia , Lipossomos/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Células A549 , Adulto , Bronquiolite Obliterante/patologia , Sistemas de Liberação de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Receptores de Hialuronatos/efeitos dos fármacos , Ácido Hialurônico/química , Lipossomos/química , Microscopia Confocal , Monócitos/efeitos dos fármacos , Fibrose Pulmonar/patologia , Fator de Crescimento Transformador beta/genética , Fator A de Crescimento do Endotélio Vascular/genética
17.
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
18.
Med Sci Monit ; 25: 6523-6531, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31471534

RESUMO

BACKGROUND Acute respiratory distress syndrome (ARDS) in infants is acute and progressive hypoxic respiratory failure caused by various extrapulmonary pathogenic factors besides cardiogenic factors. Diffuse alveolar injury and progression to pulmonary fibrosis are pathological features of ARDS. The present study sought to determine how puerarin influences the inflammatory response caused by pulmonary fibrosis in ARDS in infants. MATERIAL AND METHODS The human lung fibroblasts cell line HLF1 was treated with different concentrations of puerarin in different groups for various times. TGF-ß1 was overexpressed by TGF-ß1 (2 ng/mL) in routine experiments, and the treated cells and culture supernatant were collected for analysis in each step. Cell apoptosis was measured by flow cytometry, TUNEL assay, and detection of caspase 3 and Bcl-2. Cell proliferation was assessed by CCK-8 assay. Real-time PCR and Western blot assay were used to assess mRNA and protein levels of TGF-ß1 and Smad3, respectively. The related cytokines were assessed by ELISA. RESULTS Results showed that puerarin promoted the apoptosis and inhibited the proliferation of HLF1 cells. Caspase 3 was upregulated, whereas Bcl-2, TGF-ß1, and Smad3 were downregulated by puerarin. IL-1, IL-2, and IL-4, secreted by HLF1 cells, were reduced, but IL-10 showed the opposite trend. When TGF-ß1 was overexpressed, Smad3 was promoted, and IL-1, IL-2, and IL-4 was increased in HLF1 cells. Finally, overexpression of TGF-ß1 reversed the effect of puerarin in HLF1 cells. CONCLUSIONS Puerarin regulated the proliferation and apoptosis of pulmonary fibrosis cells, and affected the secretion of inflammatory cytokines. Thus, puerarin alleviated the inflammatory response resulting from pulmonary fibrosis by regulating the TGF-ß1/Smad3 pathway in infants with ARDS.


Assuntos
Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Fator de Crescimento Transformador beta1/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Inflamação/patologia , Interleucinas/metabolismo , Isoflavonas/farmacologia , Pulmão/embriologia , Pulmão/patologia , Fibrose Pulmonar/complicações , Fibrose Pulmonar/patologia , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/patologia
19.
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
20.
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
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