Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.394
Filtrar
1.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 231-233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093788

RESUMO

Background: A subgroup of patients with fibrotic ILD experience progression and several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. Objective: To describe a possible new phenotype of rapidly non IPF progressive fibrosing with an IPF-like outcome. Methods: Three previously fit and well patients who developed a rapidly progressive ILD and died within 6 to 7 months from the initial development of respiratory symptoms. Results: Unlike what is currently known, our patients developed a severe fibrosing ILD with an IPF-like outcome despite a) being younger than the average patient with IPF, b) having received a non-IPF MDT diagnosis, c) having a non-UIP pattern on HRCT. Moreover and similarly to IPF, they failed to respond to immunosuppressive treatment which is the preferred treatment option in these cases. Conclusion: We believe that patients who present with similar characteristics should be considered as likely to develop a phenotype of rapidly progressive ILD and be treated with antifibrotic medications instead of immunosuppressive ones according to the favourable treatment response to antifibrotic therapy observed in clinical trials of patients with progressive fibrosing ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 231-233).


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pulmão/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico , Tomografia Computadorizada por Raios X , Adulto , Antibacterianos/uso terapêutico , Progressão da Doença , Evolução Fatal , Volume Expiratório Forçado , Humanos , Imunossupressores/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Capacidade Vital
2.
Drug Discov Ther ; 14(5): 259-261, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33116043

RESUMO

Regardless of the severity of coronavirus disease 2019 (COVID-19), a high proportion of patients struggle with persistent respiratory or systemic symptoms after recovery. This is called "postCOVID syndrome", for which pulmonary fibrosis is one of the pathogenesis. Besides T-lymphocytes and macrophages, mast cells also contribute to the development of cytokine storm and thus stimulate the activity of fibroblasts. Additionally, by the exocytotic release of fibroblast-activating factors, mast cells directly facilitate the progression of pulmonary fibrosis. In our previous basic studies, anti-allergic drugs (olopatadine, ketotifen), antibiotics (clarithromycin) and corticosteroids (hydrocortisone, dexamethasone) inhibited the process of exocytosis and showed their potency as highly effective mast cell stabilizers. Given such pharmacological properties of these commonly used drugs, they may be useful in the treatment of post-COVID-19 pulmonary fibrosis and in relieving the symptoms of post-COVID syndrome.


Assuntos
Corticosteroides/uso terapêutico , Antialérgicos/uso terapêutico , Antibacterianos/uso terapêutico , Betacoronavirus/patogenicidade , Degranulação Celular/efeitos dos fármacos , Infecções por Coronavirus/virologia , Mastócitos/efeitos dos fármacos , Pneumonia Viral/virologia , Fibrose Pulmonar/tratamento farmacológico , Animais , Infecções por Coronavirus/imunologia , Interações Hospedeiro-Patógeno , Humanos , Mastócitos/imunologia , Mastócitos/virologia , Pandemias , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/virologia
3.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037188

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Assuntos
Apoptose/imunologia , Betacoronavirus/patogenicidade , Caspase 8/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Necroptose/imunologia , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Animais , Caspase 8/genética , Linhagem Celular Tumoral , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Modelos Animais de Doenças , Células Epiteliais/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Transgênicos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Fibrose Pulmonar/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Front Immunol ; 11: 2069, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973815

RESUMO

COVID-19 disease have become so far the most important sanitary crisis in the XXI century. In light of the events, any clinical resource should be considered to alleviate this crisis. Severe COVID-19 cases present a so-called cytokine storm as the most life-threatening symptom accompanied by lung fibrosis. Galectin-3 has been widely described as regulator of both processes. Hereby, we present compelling evidences on the potential role of galectin-3 in COVID-19 in the regulation of the inflammatory response, fibrosis and infection progression. Moreover, we provide a strong rationale of the utility of measuring plasma galectin-3 as a prognosis biomarker for COVID-19 patients and propose that inhibition of galectin-3 represents a feasible and promising new therapeutical approach.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Galectina 3/antagonistas & inibidores , Galectina 3/sangue , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Índice de Gravidade de Doença , Animais , Betacoronavirus/química , Biomarcadores/sangue , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Progressão da Doença , Interações Hospedeiro-Patógeno/imunologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Prognóstico , Fibrose Pulmonar/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo
5.
Toxicol Lett ; 333: 42-48, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32721576

RESUMO

Silicosis is a type of pneumoconiosis caused by the inhalation of silica dust. It is characterized by inflammation and fibrosis of the lung. Although many studies have reported that crystalline silica-inhalation into the lung initiates the immune response, activating effector cells and triggering the inflammatory cascade with subsequent elaboration of the extracellular matrix and fibrosis, the mechanism of silicosis pathogenesis remains unclear. In the present study, we established a silica inhalation-induced silicosis rat model validated by histological and cytokine analyses. RNA-seq and bioinformatic analyses showed that 600 genes were upregulated and 537 genes were downregulated in the silica-treated group. GO enrichment analysis indicates that these differentially expressed genes are enriched in several biological processes including immune response and organism remodeling. KEGG enrichment analysis showed that 53 enriched pathways were mainly associated with human diseases, immune response, signal transduction, and fibrosis process. Since alternative splicing of pre-mRNAs is also essential for the regulation of gene expression, we identified several alternative pre-mRNA splicing events in the fibrotic process. This study will provide a foundation to understand the molecular mechanism of the pulmonary fibrosis caused by silica.


Assuntos
Pulmão/efeitos dos fármacos , Fibrose Pulmonar/genética , Dióxido de Silício/toxicidade , Silicose/genética , Transcriptoma/efeitos dos fármacos , Processamento Alternativo/efeitos dos fármacos , Animais , Citocinas/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Pulmão/patologia , Masculino , Fibrose Pulmonar/imunologia , Ratos , Ratos Sprague-Dawley , Silicose/imunologia
6.
Am J Respir Crit Care Med ; 202(3): e36-e69, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32706311

RESUMO

Background: This guideline addresses the diagnosis of hypersensitivity pneumonitis (HP). It represents a collaborative effort among the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.Methods: Systematic reviews were performed for six questions. The evidence was discussed, and then recommendations were formulated by a multidisciplinary committee of experts in the field of interstitial lung disease and HP using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.Results: The guideline committee defined HP, and clinical, radiographic, and pathological features were described. HP was classified into nonfibrotic and fibrotic phenotypes. There was limited evidence that was directly applicable to all questions. The need for a thorough history and a validated questionnaire to identify potential exposures was agreed on. Serum IgG testing against potential antigens associated with HP was suggested to identify potential exposures. For patients with nonfibrotic HP, a recommendation was made in favor of obtaining bronchoalveolar lavage (BAL) fluid for lymphocyte cellular analysis, and suggestions for transbronchial lung biopsy and surgical lung biopsy were also made. For patients with fibrotic HP, suggestions were made in favor of obtaining BAL for lymphocyte cellular analysis, transbronchial lung cryobiopsy, and surgical lung biopsy. Diagnostic criteria were established, and a diagnostic algorithm was created by expert consensus. Knowledge gaps were identified as future research directions.Conclusions: The guideline committee developed a systematic approach to the diagnosis of HP. The approach should be reevaluated as new evidence accumulates.


Assuntos
Alveolite Alérgica Extrínseca/diagnóstico , Líquido da Lavagem Broncoalveolar/citologia , Exposição por Inalação , Pulmão/patologia , Linfócitos/imunologia , Fibrose Pulmonar/diagnóstico , Adulto , Alveolite Alérgica Extrínseca/complicações , Alveolite Alérgica Extrínseca/imunologia , Alveolite Alérgica Extrínseca/patologia , Biópsia , Broncoscopia , Criocirurgia , Humanos , Imunoglobulina G/imunologia , Anamnese , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Testes Sorológicos , Inquéritos e Questionários
7.
Nat Commun ; 11(1): 2795, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493933

RESUMO

The transcription factor JUN is highly expressed in pulmonary fibrosis. Its induction in mice drives lung fibrosis, which is abrogated by administration of anti-CD47. Here, we use high-dimensional mass cytometry to profile protein expression and secretome of cells from patients with pulmonary fibrosis. We show that JUN is activated in fibrotic fibroblasts that expressed increased CD47 and PD-L1. Using ATAC-seq and ChIP-seq, we found that activation of JUN rendered promoters and enhancers of CD47 and PD-L1 accessible. We further detect increased IL-6 that amplified JUN-mediated CD47 enhancer activity and protein expression. Using an in vivo mouse model of fibrosis, we found two distinct mechanisms by which blocking IL-6, CD47 and PD-L1 reversed fibrosis, by increasing phagocytosis of profibrotic fibroblasts and by eliminating suppressive effects on adaptive immunity. Our results identify specific immune mechanisms that promote fibrosis and suggest a therapeutic approach that could be used alongside conventional anti-fibrotics for pulmonary fibrosis.


Assuntos
Fibroblastos/metabolismo , Imunidade , Proteínas Proto-Oncogênicas c-jun/metabolismo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Animais , Antígeno B7-H1/metabolismo , Lavagem Broncoalveolar , Antígeno CD47/metabolismo , Fibroblastos/patologia , Humanos , Imunossupressão , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Fenótipo , Linfócitos T/imunologia
8.
Artigo em Chinês | MEDLINE | ID: mdl-32306670

RESUMO

Objective: To investigate the role of CD40/CD40L Pathway in the formation of silicosis fibrosis. Methods: Totally 64 inpatients were recruited and assigned to the silicosis group and the control group, 23 in each group. The alveolar lavage fluid was collected from all patients and isolated. The expression of CD40L protein was detected by Flow Cytometry. The level of IL-8、The IL-6、INF-γ and MCP-1 was detected by ELISA. Two groups of BALF were co-cultured with HFL-1 cells, the expression of Collagen I and α-SMA was detected by Immunohistochemistry. Results: Compared with the control group, CD40L was highly expressed on T lymphocyte cells in silicosis group (P<0.05) , and the contents of IL-8、The IL-6、INF-γand MCP-1 in Silicosis group were significantly higher than those in control group (P<0.05) . After co-culture of BALF and HFL-1 cells, the expression levels of Collagen I and α-SMA in Silicosis group were significantly higher than those in control group (P<0.05) . Conclusion: CD40-CD40L cross-linking system can promote the activation of T cells, release inflammatory factors, promote the synthesis of collagen I and α-SMA by fibroblasts, make the lung fibrous tissue proliferate, and lead to the formation of silicosis fibrosis.


Assuntos
Antígenos CD40/imunologia , Ligante de CD40/imunologia , Fibrose Pulmonar/imunologia , Silicose/imunologia , Actinas , Colágeno Tipo I , Células Matadoras Induzidas por Citocinas , Humanos , Pulmão/fisiopatologia , Linfócitos T/imunologia
9.
Sci Rep ; 10(1): 6647, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313071

RESUMO

Crystalline silica (quartz) is known to induce silicosis and cancer in the lungs. In the present study, we investigated the relationship between quartz-induced chronic inflammation and lung carcinogenesis in rat lungs after a single exposure to quartz. F344 rats were treated with a single intratracheal instillation (i.t.) of quartz (4 mg/rat), and control rats were treated with a single i.t. of saline. After 52 or 96 weeks, the animals were sacrificed, and the lungs and other organs were used for analyses. Quartz particles were observed in the lungs of all quartz-treated rats. According to our scoring system, the lungs of rats treated with quartz had higher scores for infiltration of lymphocytes, macrophages and neutrophils, oedema, fibrosis, and granuloma than the lungs of control rats. After 96 weeks, the quartz-treated rats had higher incidences of adenoma (85.7%) and adenocarcinoma (81.0%) than control rats (20% and 20%, respectively). Quartz-treated and control rats did not show lung neoplastic lesions at 52 weeks after treatment. The number of lung neoplastic lesions per rat positively correlated with the degree of macrophage and lymphocyte infiltration, oedema, fibrosis, and lymph follicle formation around the bronchioles. In conclusion, single i.t. of quartz may induce lung cancer in rat along with chronic inflammation.


Assuntos
Adenocarcinoma/induzido quimicamente , Carcinogênese/efeitos dos fármacos , Neoplasias Pulmonares/induzido quimicamente , Fibrose Pulmonar/induzido quimicamente , Quartzo/administração & dosagem , Silicose/etiologia , Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Animais , Movimento Celular/efeitos dos fármacos , Edema/induzido quimicamente , Edema/imunologia , Edema/patologia , Granuloma/induzido quimicamente , Granuloma/imunologia , Granuloma/patologia , Inflamação , Intubação Intratraqueal , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Ratos , Ratos Endogâmicos F344 , Silicose/imunologia , Silicose/patologia
10.
Immunity ; 52(3): 542-556.e13, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32187520

RESUMO

Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.


Assuntos
Apoptose/imunologia , Núcleo Celular/imunologia , Exossomos/imunologia , Fibrose Pulmonar/imunologia , Proteínas de Ligação a RNA/imunologia , Animais , Apoptose/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Quimiocina CXCL12/imunologia , Quimiocina CXCL12/metabolismo , Exossomos/genética , Exossomos/metabolismo , Regulação da Expressão Gênica/imunologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/metabolismo , Células NIH 3T3 , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
11.
Arthritis Res Ther ; 22(1): 20, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32033616

RESUMO

BACKGROUND: Interstitial lung disease (ILD) is a serious complication of connective tissue diseases (CTDs). Although immune dysregulation triggered by genetic and environmental factors is thought to provoke inflammation and subsequent fibrosis, precise mechanisms of these processes remain unclear. Recent reports suggest that activation of aryl hydrocarbon receptor (AhR) signals by various ligands such as tryptophan derivatives can induce hyper-immune responses and are involved in autoimmunity. We investigated the effects of AhR signals on the process of lung fibrosis and changes in immunological features using a bleomycin (BLM)-induced lung fibrosis mouse model. METHODS: BLM was administered intratracheally to C57BL/6JJcl mice and either 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (FICZ), a natural AhR ligand, or vehicle was subsequently injected intraperitoneally on day 0, 1, and 2 from BLM administration. Mice were sacrificed at week 3, and lung fibrosis was quantified by the histological changes using the Ashcroft score and deposition of soluble collagen levels in the lung using Sircol assay. The population of immune cells infiltrated into the lungs was analyzed using flow cytometry. RESULTS: Both the Ashcroft score and soluble collagen level in FICZ-treated mice were significantly lower than those in the vehicle group. Moreover, the survival rate of FICZ-treated mice was significantly higher than that of control mice during the 3 weeks after treatment. Interestingly, flow cytometric analysis revealed that the number of CD4+Foxp3+ regulatory T cells (Tregs) was significantly increased and CD4+IFNγ+ and γδ+IL-17A+ T cells were decreased in the lungs of FICZ-treated mice, while the total number of T, B, and NK cells were unaffected by FICZ treatment. CONCLUSIONS: Our findings suggest that stimulation of AhR signals attenuated lung fibrosis by increasing Tregs and suppressing inflammatory T cell subsets in a BLM-induced fibrosis model. AhR signaling pathways may therefore be useful therapeutic targets for connective tissue disease-associated ILD.


Assuntos
Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Antibióticos Antineoplásicos/toxicidade , Bleomicina/toxicidade , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/metabolismo
12.
Mol Immunol ; 120: 83-92, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32106023

RESUMO

Pulmonary fibrosis is a progressive chronic inflammatory lung disease whose pathogenesis is complicated. Platelets and neutrophils play important roles in the progression of pulmonary inflammation. We have reported that cangrelor, a non-sepesific GPR17 antagonist, alleviates pulmonary fibrosis partly by inhibiting macrophage inflammation in mice. Cangrelor is also a well-known anti-platelet agent. To test whether cangrelor mitigated pulmonary fibrosis partly through the inhibition of platelets, bleomycin (BLM) was used to induce pulmonary fibrosis in C57BL/6 J mice. We found that cangrelor (10 mg/kg) not only significantly decreased BLM-induced release of inflammatory cytokines (PF4, CD40 L and MPO), but also decreased the increment of platelets, neutrophils and platelet-neutrophil aggregates in the fibrotic lung and in the peripheral blood of BLM-treated mice. In addition, cangrelor decreased the number of CD40 and MPO double positive neutrophils and the expression level of CD40 in BLM-treated mouse lungs. Based on these results we conclude that cangrelor alleviates BLM-induced lung inflammation and pulmonary fibrosis in mice, partly through inhibition of platelet activation, therefore reducing the infiltration of neutrophils due to the adhesion of platelets and neutrophils mediated by CD40 - CD40 L interaction. Cangrelor could be a potential therapeutic medicine for pulmonary fibrosis.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Ativação Plaquetária/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Monofosfato de Adenosina/uso terapêutico , Animais , Bleomicina/toxicidade , Antígenos CD40/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ativação Plaquetária/imunologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/imunologia
13.
Annu Rev Med ; 71: 263-276, 2020 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986085

RESUMO

Interleukin (IL)-11 is upregulated in a wide variety of fibro-inflammatory diseases such as systemic sclerosis, rheumatoid arthritis, pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug-induced liver injury, and nonalcoholic steatohepatitis. IL-11 is a member of the IL-6 cytokine family and has several distinct properties that define its unique and nonredundant roles in disease. The IL-11 receptor is highly expressed on stromal, epithelial and polarized cells, where noncanonical IL-11 signaling drives the three pathologies common to all fibro-inflammatory diseases-myofibroblast activation, parenchymal cell dysfunction, and inflammation-while also inhibiting tissue regeneration. This cytokine has been little studied, and publications on IL-11 peaked in the early 1990s, when it was largely misunderstood. Here we describe recent advances in our understanding of IL-11 biology, outline how misconceptions as to its function came about, and highlight the large potential of therapies targeting IL-11 signaling for treating human disease.


Assuntos
Fibrose/imunologia , Inflamação/imunologia , Interleucina-11/imunologia , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Interleucina-11/metabolismo , Interleucina-11/fisiologia , Interleucina-6/imunologia , Nefropatias/imunologia , Nefropatias/metabolismo , Nefropatias/patologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Miofibroblastos/imunologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Neoplasias/imunologia , Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Proteínas Recombinantes , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Pele/imunologia , Pele/metabolismo , Pele/patologia
14.
Exp Cell Res ; 386(1): 111700, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678213

RESUMO

The immune system is felt to play an essential role in pulmonary fibrosis (PF). CD4+CD25+ regulatory T cells (Tregs) are crucial in maintaining immune tolerance and immune homeostasis, but their role in the pathogenesis of PF is controversial and still unclear. We here explored the relationship between peripheral blood CD4+CD25+ Tregs and the course of bleomycin-induced PF in mice. Mouse PF models were established by intratracheal instillation of bleomycin. Lung histology, hydroxyproline, Th1/Th2 balanc, CD4+CD25+ Tregse were analyzed at the 3rd,7th,14th,21st and 28th days after instillation. CD4+CD25+ Tregs were also transferred into mice with or without PF by tail vein injection. The trend of CD4+CD25+ Tregs changes was increased firstly, decreased, increased again from 7th to 28th days after bleomycin instillation, which had great relevance with alveolitis and fibrosis scores. There also were high Th1 polarization index from 3rd to 14th days and high Th2 polarization index at 21st and 28th days after bleomycin treatment. CD4+CD25+ Tregs could promote the secretion of Th2 cytokines and inhibit the secretion of Th1 cytokines, allow the Th1/Th2 balance to Th2 direction in PF. Moreover, preventive adoptive transfer of CD4+CD25+ Tregs may ameliorate the process of PF, while acute adoptive transfer of CD4+CD25+ Tregs may aggravate the process of PF. These findings suggested that the dynamic changes of CD4+CD25+ Tregs as dependent factor might designate a different course of PF induced by bleomycin in mice, and might be a selected drug use indicator for therapy of PF.


Assuntos
Fibrose Pulmonar/imunologia , Linfócitos T Reguladores/imunologia , Animais , Bleomicina/toxicidade , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Camundongos , Fibrose Pulmonar/sangue , Fibrose Pulmonar/etiologia , Linfócitos T Reguladores/citologia
15.
Inflammation ; 43(1): 109-122, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31696351

RESUMO

Visfatin acts as a significant regulator of inflammatory cytokines. However, the immunological response and therapeutic effects of visfatin under bacterial stress in murine lung tissue are still not clear. To investigate the role of visfatin on lipopolysaccharide (LPS)-induced acute lung injury (ALI), thirty Kunming mice were divided into Saline, LPS, and LPS + visfatin groups. After routine blood examination, the effects of visfatin on inflammatory cytokines, lung tissue structure, and expression of inflammatory mediators were explored through hematoxylin-eosin (H&E), Masson and immunohistochemical staining, quantitative polymerase chain reaction (Q-PCR), and Western blotting. Compared with the Saline group, neutrophil percentage, peripheral blood neutrophil count, and the ratio of lymphocyte count (NLR) were upregulated in LPS group. Moreover, Masson staining showed alterations in lung tissue structure; the mRNA level of different cytokines (IL-6, IL-1ß, TNF-α, IL-10, TLR4, IFN-γ) was upregulated; and the protein expression of interleukin (IL)-6, myeloperoxidase (MPO), and transforming growth factor-ß1 (TGF-ß) was significantly (p < 0.05) different in LPS group. Compared with LPS group, neutrophil percentage significantly decreased (p < 0.01), the numbers of lymphocytes significantly (p < 0.05) increased, NLR decreased, Masson staining of the lung was extremely different (p < 0.01), the structure of the lung was slightly damaged, and the myeloperoxidase values of lung showed no differences in LPS + visfatin. Hence, visfatin inhibits the lung inflammation induced by ALI. During the ALI, visfatin acts by decreasing NLR, downregulated the expression of MPO, enhanced antioxidant capacity, and regulated the inflammatory factors IL-1ß, IL-6, IL-10, and TNF-α to reduce the lung injury.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Citocinas/farmacologia , Pulmão/efeitos dos fármacos , Nicotinamida Fosforribosiltransferase/farmacologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Peroxidase/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/prevenção & controle , Fator de Crescimento Transformador beta1/metabolismo
16.
Microbes Infect ; 22(3): 137-143, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31770592

RESUMO

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by thermally dimorphic fungi of the genus Paracoccidioides that affects predominantly 30-60-year-old male rural workers. The main clinical forms of the disease are acute/subacute, chronic (CF); almost all CF patients develop pulmonary fibrosis, and they also exhibit emphysema due to smoke. An important cytokine in this context, IL-1ß, different from the others, is produced by an intracellular multimolecular complex called inflammasome that is activated by pathogens and/or host signs of damage. Inflammasome has been recognized for its contribution to chronic inflammatory diseases, from that, we hypothesized that this activation could be involved in paracoccidioidomycosis, contributing to chronic inflammation. While inflammasome activation has been demonstrated in experimental models of Paracoccidioides brasiliensis infection, no information is available in patients, leading us to investigate the participation of NLRP3-inflammasome machinery in CF/PCM patients from a Brazilian endemic area. Our findings showed increased priming in mRNA levels of NLRP3 inflammasome genes by monocytes of PCM patients in vitro than healthy controls. Similar intracellular protein expression of NLRP3, CASP-1, ASC, and IL-1ß were also observed in freshly isolated monocytes of PCM patients and smoker controls. Increased expression of NLRP3 and ASC was observed in monocytes from PCM patients under hypoxia in comparison with smoker controls. For the first time, we showed that primed monocytes of CF-PCM patients were associated with enhanced expression of components of NLRP3-inflammasome due to smoke. Also, hypoxemia boosted this machinery. These findings reinforce the systemic low-grade inflammation activation observed in PCM during and after treatment.


Assuntos
Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Paracoccidioidomicose/imunologia , Fumar , Hipóxia Celular , Humanos , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Pneumopatias Fúngicas/microbiologia , Monócitos/microbiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Paracoccidioides , Paracoccidioidomicose/microbiologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/microbiologia
17.
Can Respir J ; 2019: 7262065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885749

RESUMO

Objective: The absolute and relative changes of peripheral NK and T subsets are unclear in rheumatoid arthritis (RA) associated with pulmonary interstitial fibrosis (RA-ILD). To investigate the clinical risk factors, especially the changes of lymphocyte subsets, in RA-ILD in order to make early diagnosis and achieve prevention of the pulmonary interstitial lesions. Methods: A total of 100 RA and 100 RA-ILD patients were enrolled. Rheumatoid factor, anti-cyclic citrulline peptide antibody, erythrocyte sedimentation rate, immunoglobulin, and C-reactive protein were examined. The percentage and absolute number of NK, T, B, Treg, Th1, Th2, and Th17 cells in peripheral blood were determined by flow cytometry. Results: RA-ILD is more common in older and male RA patients and/or those with higher autoantibody titers. Flow cytometry showed that the absolute and relative numbers of CD56+ NK cells were significantly higher in RA-ILD (280.40 ± 180.51 cells/µl vs. 207.66 ± 148.57 cells/µl; 16.62 ± 8.56% vs. 12.11 ± 6.47%), whereas the proportion of T cells and CD4+ T cells was lower in peripheral blood of RA-ILD patients (69.82 ± 9.30%; 39.44 ± 9.87 cells/µl) than that in RA patients (74.45 ± 8.72%; 43.29 ± 9.10 cells/µl). Conclusions: The occurrence of RA-ILD is closely related to the older male patients with high titer of various self-antibodies. Imbalance of CD3-CD56+ NK cells and T cells with other subsets were found in RA-ILD patients, which, together with older age, male, and high levels of autoantibodies should be considered as risk factors of pulmonary interstitial lesions.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Células Matadoras Naturais/imunologia , Doenças Pulmonares Intersticiais/imunologia , Fibrose Pulmonar/imunologia , Fator Reumatoide/imunologia , Linfócitos T/imunologia , Adulto , Fatores Etários , Idoso , Artrite Reumatoide/complicações , Linfócitos B/imunologia , Sedimentação Sanguínea , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Doenças Pulmonares Intersticiais/complicações , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/complicações , Fatores Sexuais , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
18.
Sci Adv ; 5(11): eaay1971, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723606

RESUMO

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-α-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-ß (α-TGF-ß) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos/uso terapêutico , Colágeno/antagonistas & inibidores , Inflamação/tratamento farmacológico , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Anticorpos/imunologia , Anticorpos/metabolismo , Colágeno/imunologia , Colágeno/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular/métodos , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Sialoglicoproteínas/imunologia , Sialoglicoproteínas/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Chem Res Toxicol ; 32(11): 2192-2203, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31642316

RESUMO

Silicosis is a kind of irreversible pulmonary fibrosis induced by the long-term inhalation of silica particles. The therapeutic strategy based on the microRNAs might be an effective way for the treatment of silicosis. Our previous miRNA microarray data indicated that miR-326 was decreased in the mouse lung tissues of silica-induced pulmonary fibrosis. However, the specific functions of miR-326 on silica-induced pulmonary fibrosis remain unclear. The objective was to determine the expression and the biological effects of miR-326 in silica-induced pulmonary fibrosis. Methods included mouse models of silica-induced pulmonary fibrosis and miR-326 intervention that were established separately to explore the effect of miR-326 in vivo. The cell models of SiO2-treated lung epithelial cells (HBE and A549) and TGF-ß1-stimulated lung fibroblast cells (MRC-5 and NIH/3T3) were used to investigate the mechanism of miR-326 in vitro. Hematoxylin and eosin staining was used to evaluate the severity and distribution of fibrosis of mouse lung tissues. Western blot and immunofluorescence assays were performed to measure the downstream molecules of miR-326. Transmission electron microscopy pictures showed the autophagy activity. The results showed miR-326 is down-regulated in the fibrotic lung tissues of silica-treated mice, while increased expression of miR-326 attenuates silica-induced pulmonary fibrosis in vivo. Tumor necrosis factor superfamily-14 (TNFSF14) and polypyrimidine tract-binding protein 1 (PTBP1) are identified as the targets of miR-326. MiR-326 dampens pulmonary inflammation through targeting TNFSF14 and promotes autophagy activity of fibroblasts through targeting PTBP1. LncRNA HOTAIR facilitates inflammation via sponging miR-326. In conclusion, we demonstrate that miR-326 inhibits inflammation and promotes autophagy activity by targeting TNFSF14 and PTBP1 separately to alleviate silica-induced pulmonary fibrosis. Our results might shed new light on the therapeutic strategies for silica-induced pulmonary fibrosis.


Assuntos
Autofagia/efeitos dos fármacos , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , MicroRNAs/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Fibrose Pulmonar/imunologia , Dióxido de Silício/toxicidade , Silicose/imunologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Células A549 , Animais , Autofagia/genética , Autofagia/imunologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Células NIH 3T3 , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , RNA Longo não Codificante/metabolismo , Silicose/etiologia , Silicose/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...