Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
1.
Ecotoxicol Environ Saf ; 274: 116234, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38503107

RESUMO

BACKGROUND: Studies have shown that short- and long-term exposure to particulate matter (PM) can increase the risk of asthma morbidity and mortality. However, the effect of medium-term exposure remains unknown. We aim to examine the effect of medium-term exposure to size-fractioned PM on asthma exacerbations among asthmatics with poor medication adherence. METHODS: We conducted a longitudinal study in China based on the National Mobile Asthma Management System Project that specifically and routinely followed asthma exacerbations in asthmatics with poor medication adherence from April 2017 to May 2019. High-resolution satellite remote-sensing data were used to estimate each participant's medium-term exposure (on average 90 days) to size-fractioned PM (PM1, PM2.5, and PM10) based on the residential address and the date of the follow-up when asthma exacerbations (e.g., hospitalizations and emergency room visits) occurred or the end of the follow-up. The Cox proportional hazards model was employed to examine the hazard ratio of asthma exacerbations associated with each PM after controlling for sex, age, BMI, education level, geographic region, and temperature. RESULTS: Modelling results revealed nonlinear exposure-response associations of asthma exacerbations with medium-term exposure to PM1, PM2.5, and PM10. Specifically, for emergency room visits, we found an increased hazard ratio for PM1 above 22.8 µg/m3 (1.060, 95 % CI: 1.025-1.096, per 1 µg/m3 increase), PM2.5 above 38.2 µg/m3 (1.032, 95 % CI: 1.010-1.054), and PM10 above 78.6 µg/m3 (1.019, 95 % CI: 1.006-1.032). For hospitalizations, we also found an increased hazard ratio for PM1 above 20.3 µg/m3 (1.055, 95 % CI: 1.001-1.111) and PM2.5 above 39.2 µg/m3 (1.038, 95 % CI: 1.003-1.074). Furthermore, the effects of PM were greater for a longer exposure window (90-180 days) and among participants with a high BMI. CONCLUSION: This study suggests that medium-term exposure to PM is associated with an increased risk of asthma exacerbations in asthmatics with poor medication adherence, with a higher risk from smaller PM.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Asma , Humanos , Material Particulado/toxicidade , Estudos Longitudinais , Exposição Ambiental/análise , Asma/tratamento farmacológico , Asma/epidemiologia , Asma/induzido quimicamente , China/epidemiologia , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/análise
2.
Chin Med J (Engl) ; 136(23): 2839-2846, 2023 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-37464421

RESUMO

BACKGROUND: The presence of fibrosis is a criterion for subtype classification in the newly updated hypersensitivity pneumonitis (HP) guidelines. The present study aimed to summarize differences in clinical characteristics and prognosis of non-fibrotic hypersensitivity pneumonitis (NFHP) and fibrotic hypersensitivity pneumonitis (FHP) and explore factors associated with the presence of fibrosis. METHODS: In this prospective cohort study, patients diagnosed with HP through a multidisciplinary discussion were enrolled. Collected data included demographic and clinical characteristics, laboratory findings, and radiologic and histopathological features. Logistic regression analyses were performed to explore factors related to the presence of fibrosis. RESULTS: A total of 202 patients with HP were enrolled, including 87 (43.1%) NFHP patients and 115 (56.9%) FHP patients. Patients with FHP were older and more frequently presented with dyspnea, crackles, and digital clubbing than patients with NFHP. Serum levels of carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 153, gastrin-releasing peptide precursor, squamous cell carcinoma antigen, and antigen cytokeratin 21-1, and count of bronchoalveolar lavage (BAL) eosinophils were higher in the FHP group than in the NFHP group. BAL lymphocytosis was present in both groups, but less pronounced in the FHP group. Multivariable regression analyses revealed that older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors for the development of FHP. Twelve patients developed adverse outcomes, with a median survival time of 12.5 months, all of whom had FHP. CONCLUSIONS: Older age, <20% of lymphocyte in BAL, and ≥1.75% of eosinophil in BAL were risk factors associated with the development of FHP. Prognosis of patients with NFHP was better than that of patients with FHP. These results may provide insights into the mechanisms of fibrosis in HP.


Assuntos
Alveolite Alérgica Extrínseca , Humanos , Líquido da Lavagem Broncoalveolar , Estudos Prospectivos , Alveolite Alérgica Extrínseca/diagnóstico , Fibrose , Carboidratos
3.
Exp Biol Med (Maywood) ; 248(14): 1181-1190, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37452708

RESUMO

Sarcoidosis is a granulomatous disease of unknown etiology, with limited therapeutic options. Chronic sarcoidosis can result in pulmonary fibrosis and can be lethal. Enhanced expression of pro-inflammatory cytokines, such as interleukin-17A (IL-17A), has been observed in sarcoid granulomas in humans. However, the role of IL-17A in the pathogenesis of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis and its potential therapeutic effects remain unclear. This study investigated whether IL-17A is critical in granulomatosis and its role in chronic inflammation in a profibrotic manner. Wild-type and IL-17A-knockout C57BL/6 mice were repeatedly challenged with heat-killed Propionibacterium acnes (PA) to induce sarcoidosis-like granulomata and sarcoidosis-related pulmonary fibrosis. Wild-type mice with granulomatosis were treated with anti-IL-17A antibody. Administration of PA enhanced the expression of IL-17A, granulomatosis, and fibrosis in mouse lungs after boost stimulation. Neither granulomata nor fibrosis were observed in IL-17A-knockout mice, even in the presence of interferon-γ enhancement. Neutralizing IL-17A antibody reduced inflammatory cells in bronchoalveolar lavage fluid and ameliorated both granulomatosis and fibrosis in sarcoidosis mice. In conclusion, our data demonstrate that IL-17A plays a critical role in PA-induced sarcoidosis-like inflammation in both granulomatosis inflammation and disease progression to pulmonary fibrosis, thus providing novel insights into the treatment of chronic sarcoidosis or sarcoidosis-related pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Sarcoidose , Animais , Humanos , Camundongos , Granuloma/patologia , Inflamação , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Propionibacterium acnes/metabolismo
4.
Front Immunol ; 14: 1185443, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37520566

RESUMO

Rationale: Sarcoidosis is a granulomatous interstitial lung disease involving a complex interplay among different cluster of differentiation 4 (CD4+) thymus cell (T-cell) subsets. Originally described as a type 1 T-helper (Th1) inflammatory disease, recent evidence suggests that both effector and regulatory T-cell subgroups play a critical role in sarcoidosis, but this remains controversial. Objectives: We aimed to investigate the distribution of CD4+ T-cell subpopulations in sarcoidosis patients and its potential associations with clinical disease activity and a radiographic fibrotic phenotype. Methods: We measured the frequencies of regulatory T cells (Tregs), Th1, Th17, and Th17.1 cells in the peripheral blood and/or bronchoalveolar lavage fluid (BALF) of 62 sarcoidosis patients, 66 idiopathic pulmonary fibrosis (IPF) patients, and 41 healthy volunteers using flow cytometry. We also measured the changes in these T-cell subpopulations in the blood at the follow-up visits of 11 sarcoidosis patients. Measurements and results: An increased percentage of Tregs was observed in the peripheral blood of sarcoidosis patients, with a positive association to disease activity and a fibrotic radiographic phenotype. We found a higher frequency of Tregs, a lower proportion of Th17.1 cells, and a lower ratio of Th17.1 cells to total Tregs in the peripheral blood of both active and fibrotic sarcoidosis patients, compared with IPF patients or healthy donors. In contrast, a lower frequency of Tregs and a higher proportion of Th17.1 cells was found in the BALF of sarcoidosis patients than in that of IPF patients. There was an imbalance of Tregs and Th17.1 cells between the peripheral blood and BALF in sarcoidosis patients. Following immunoregulatory therapy, the proportion of circulating Tregs in sarcoidosis patients decreased. Conclusion: A higher proportion of Tregs in the peripheral blood of sarcoidosis patients was related to disease activity, fibrotic phenotype, and the need for immunoregulatory therapy. The imbalanced distribution of Tregs and Th17.1 cells in patients' peripheral blood and BALF suggests that the lung microenvironment has an effect on the immunological pathogenesis of sarcoidosis. Therefore, further studies on the functional analysis of Tregs and Th17.1 cells in sarcoidosis patients are warranted.


Assuntos
Fibrose Pulmonar Idiopática , Sarcoidose , Humanos , Linfócitos T Reguladores , Líquido da Lavagem Broncoalveolar , Pulmão/patologia , Fenótipo , Fibrose Pulmonar Idiopática/metabolismo
5.
CNS Neurosci Ther ; 29(10): 2857-2872, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37063066

RESUMO

INTRODUCTION: Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as motor, sensory, and autonomic dysfunction below the level of damage. Our previous studies confirmed the ability of zinc to protect mitochondria, protect neurons and promote spinal cord recovery. However, the role of zinc in Parthanatos is unknown. AIM: We investigated the effects of zinc in Parthanatos from oxidative stress and mitophagy. We elucidated the role of SIRT3 in providing new ideas for treating spinal cord injury. THE RESULTS: Zinc protected SCI mice by regulating Parthanatos. On the one hand, zinc eliminated ROS directly through SIRT3 deacetylation targeting SOD2 to alleviate Parthanatos. On the other hand, zinc eliminated ROS indirectly through SIRT3-mediated promotion of mitophagy to alleviate Parthanatos. CONCLUSION: Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3-mediated anti-oxidative stress and mitophagy.


Assuntos
Parthanatos , Sirtuína 3 , Traumatismos da Medula Espinal , Camundongos , Animais , Sirtuína 3/metabolismo , Zinco/farmacologia , Espécies Reativas de Oxigênio , Mitofagia , Estresse Oxidativo/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Medula Espinal/metabolismo
6.
Clin Respir J ; 17(9): 831-840, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36437511

RESUMO

INTRODUCTION: The GAP model was widely used as a simple risk "screening" method for patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: We sought to validate the GAP model in Chinese patients with IPF to evaluate whether it can accurately predict the risk for mortality. METHODS: A total of 212 patients with IPF diagnosed at China-Japan Friendship Hospital from 2015 to 2019 were enrolled. The latest follow-up ended in September 2022. Cumulative mortality of each GAP stage was calculated and compared based on Fine-Gray models for survival, and lung transplantation was treated as a competing risk. The performance of the model was evaluated in terms of both discrimination and calibration. RESULTS: The cumulative mortality in patients with GAP stage III was significantly higher than that in those with GAP stage I or II (Gray's test p < 0.0001). The Harrell c-index for the GAP calculator was 0.736 (95% CI: 0.667-0.864). The discrimination for the GAP staging system were similar with that for the GAP calculator. The GAP model overestimated the mortality rate at 1- and 2-year in patients classified as GAP stage I (6.90% vs. 1.77% for 1-year, 14.20% vs. 6.78% for 2-year). CONCLUSIONS: Our findings indicated that the GAP model overestimated the mortality rate in mild group.


Assuntos
Fibrose Pulmonar Idiopática , Transplante de Pulmão , Humanos , China/epidemiologia , População do Leste Asiático , Fibrose Pulmonar Idiopática/diagnóstico
7.
Front Med (Lausanne) ; 9: 955125, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36425108

RESUMO

Objectives: We sought to evaluate the prognostic value of blood routine parameters and biochemical parameters, especially inflammation-related biomarkers, and establish an inflammation-related prognostic model in Chinese patients with idiopathic pulmonary fibrosis (IPF). Material/methods: Patients diagnosed as IPF at Beijing Chaoyang Hospital and aged 40 years and older were consecutively enrolled from June 2000 to March 2015, and finally, a total of 377 patients were enrolled in the derivation cohort. The follow-up ended in December 2016. We used Cox proportional hazard model to calculate the hazard ratio (HR) and establish the prognostic model. The discrimination and calibration of the prognostic model were evaluated in an independent validation cohort enrolled from China-Japan Friendship Hospital between January 2015 and December 2019. Results: Multivariate analysis revealed that patients with elevated monocyte-to-red blood cell count ratio (MRR) and monocyte counts showed increased risk of mortality. The clinical-physiological-biomarker (CPB) index and CPB stage we established in this study were a significant predictor, and the C-index for CPB index and CPB stage in the validation cohort was 0.635 (95% CI: 0.558-0.712) and 0.619 (95% CI: 0.544-0.694), respectively. Patients in CPB stage III had the poorest survival. Conclusion: We developed and validated a new inflammation-related prognostic model (CPB index and CPB stage) which was integration of age, gender, FVC (%, predicted), DLCO (%, predicted), Charlson Comorbidity Index, and blood monocyte counts. This prediction model exhibited strong ability in predicting mortality in Chinese patients with IPF.

8.
Front Med (Lausanne) ; 9: 960266, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36203777

RESUMO

Sarcoidosis is a granulomatous disease of unknown etiology, immunologically characterized by a Th1 immune response. Transcriptome-wide expression studies in various types of sarcoid tissues contributed to better understanding of disease mechanisms. We performed a systematic database search on Gene Expression Omnibus (GEO) and utilized transcriptomic data from blood and sarcoidosis-affected tissues in a meta-analysis to identify a cross-tissue, cross-platform signature. Datasets were further separated into training and testing sets for development of a diagnostic classifier for sarcoidosis. A total of 690 differentially expressed genes were identified in the analysis among various tissues. 29 of the genes were robustly associated with sarcoidosis in the meta-analysis both in blood and in lung-associated tissues. Top genes included LINC01278 (P = 3.11 × 10-13), GBP5 (P = 5.56 × 10-07), and PSMB9 (P = 1.11 × 10-06). Pathway enrichment analysis revealed activated IFN-γ, IL-1, and IL-18, autophagy, and viral infection response. IL-17 was observed to be enriched in peripheral blood specific signature genes. A 16-gene classifier achieved excellent performance in the independent validation data (AUC 0.711-0.964). This study provides a cross-tissue meta-analysis for expression profiles of sarcoidosis and identifies a diagnostic classifier that potentially can complement more invasive procedures.

9.
J Cell Mol Med ; 26(22): 5728-5741, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36308405

RESUMO

The dysfunction of type II alveolar epithelial cells (AECIIs), mainly manifested by apoptosis, has emerged as a major component of idiopathic pulmonary fibrosis (IPF) pathophysiology. A pivotal mechanism leading to AECIIs apoptosis is mitochondrial dysfunction. Recently, interleukin (IL)-17A has been demonstrated to have a pro-fibrotic role in IPF, though the mechanism is unclear. In this study, we report enhanced expression of IL-17 receptor A (IL-17RA) in AECIIs in lung samples of IPF patients, which may be related to the accumulation of mitochondria in AECIIs of IPF. Next, we investigated this relationship in bleomycin (BLM)-induced PF murine model. We found that IL-17A knockout (IL-17A-/- ) mice exhibited decreased apoptosis levels of AECIIs. This was possibly a result of the recovery of mitochondrial morphology from the improved mitochondrial dynamics of AECIIs, which eventually contributed to alleviating lung fibrosis. Analysis of in vitro data indicates that IL-17A impairs mitochondrial function and mitochondrial dynamics of mouse primary AECIIs, further promoting apoptosis. PTEN-induced putative kinase 1 (PINK1)/Parkin signal-mediated mitophagy is an important aspect of mitochondria homeostasis maintenance. Our data demonstrate that IL-17A inhibits mitophagy and promotes apoptosis of AECIIs by decreasing the expression levels of PINK1. We conclude that IL-17A exerts its pro-fibrotic effects by inducing mitochondrial dysfunction in AECIIs by disturbing mitochondrial dynamics and inhibiting PINK1-mediated mitophagy, thereby leading to apoptosis of AECIIs.


Assuntos
Células Epiteliais Alveolares , Fibrose Pulmonar Idiopática , Animais , Camundongos , Células Epiteliais Alveolares/metabolismo , Bleomicina/farmacologia , Células Epiteliais/metabolismo , Fibrose , Homeostase , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Interleucina-17/metabolismo , Pulmão/patologia , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo
10.
BMC Pulm Med ; 22(1): 297, 2022 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-35918677

RESUMO

BACKGROUND: Recent years, idiopathic pulmonary fibrosis (IPF) is thought to be a disease of alveoli as well as small airways. This study aimed to demonstrate the clinical feature, predictor, and prognosis of small airway dysfunction (SAD) in Chinese patients with IPF. METHODS: We enrolled 416 patients with IPF who hospitalized in Beijing Chao-Yang Hospital from 2000 to 2014 in this study, and the follow-up ended at December 2016. We collected demographic information, clinical examination results, spirometry results, HRCT results, and blood gas results during the study. Logistic regression analysis was used to identify the predictor for SAD. The COX proportional hazard model was used to analysis the prognosis effect of SAD. RESULTS: Among all the participants, 165 (39.66%) patients had SAD. FEV1 (% predicted) and FEV3/FVC were significantly associated with SAD in patients with IPF. IPF patients with lower FEV1 (% predicted, OR 30.04, 95% CI 9.61-93.90) and FEV3/FVC (OR 77.76, 95% CI 15.44-391.63) had increased risk for SAD. Patients with SAD were associated with significantly increased risk of mortality in patients with IPF (HR 1.73, 95% CI 1.02-2.92), as well as in IPF patients without other pulmonary comorbidities (COPD, emphysema, and asthma). CONCLUSIONS: Spirometry-defined SAD was like 40% in patients with IPF. Lower FEV1 (% predicted) and FEV3/FVC were main predictors for SAD. IPF patients with SAD showed poorer prognosis.


Assuntos
Fibrose Pulmonar Idiopática , Enfisema Pulmonar , China , Humanos , Pulmão/diagnóstico por imagem , Modelos de Riscos Proporcionais , Estudos Retrospectivos
11.
Clin Respir J ; 16(3): 234-243, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35081277

RESUMO

BACKGROUND: Serum Krebs von den Lungen-6 (KL-6) has been reported to be elevated in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The aim of this study was to evaluate the diagnostic value of KL-6 and whether the expression value of KL-6 could indicate the severity of the disease in IPF patients. To address this question, it is necessary to see whether the patients' physical characteristics and other clinical conditions could affect the baseline KL-6 level. DESIGN: We conducted a study of 100 patients who were diagnosed with IPF. Lung function, computed tomography (CT), and serological lab tests data were analyzed. RESULTS: The tests showed that there is a significant elevation of KL-6 in IPF patients compared with other interstitial lung disease (ILD) and healthy controls. It was noted that serum KL-6 is a stable biomarker not affected by lung infection and smoking, though IPF patients with antinuclear antibody (ANA) showed higher KL-6 levels. KL-6, in conjunction with poor pulmonary function and higher radiological fibrosis scores, indicates the severity of the disease but not poor survival. CONCLUSIONS: It is identified that serum KL-6 is a useful noninvasive biomarker to help improve the certainty of IPF diagnosis from other interstitial lung disease and assist evaluation of disease severity and prognosis.


Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Biomarcadores , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Prognóstico
12.
Front Med (Lausanne) ; 9: 1047783, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36714123

RESUMO

Acute fibrinous and organizing pneumonia (AFOP) is a lung disease with an unusual pathological pattern. The definitive diagnosis of AFOP relies on pathological evidence of intra-alveolar fibrin exudate, lymphoplasmacytic infiltrate, and the absence of a hyaline membrane. Furthermore, its etiology is difficult to confirm, and corticosteroids are usually effective. Herein, we report the case of a young male who presented with high fever, hemocytopenia, and consolidation in both lungs. The initial misdiagnosis was community-acquired pneumonia. Subsequently, a lung biopsy revealed abundant fibrin and fibroblast exudates in the alveolar spaces, indicating AFOP. In addition, bone marrow biopsy and karyotype analysis demonstrated that the patient simultaneously had myelodysplastic syndrome (MDS) and hemophagocytic lymphohistiocytosis. In this case, the AFOP was considered secondary to MDS; however, the disease did not respond to glucocorticoid treatment or chemotherapy. Hence, AFOP should be considered in patients with underlying hematological diseases, and early identification and diagnosis are important. Furthermore, the management of patients with severe AFOP requires further investigation.

13.
Am J Respir Cell Mol Biol ; 64(1): 115-125, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33074715

RESUMO

Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-ß1 (transforming growth factor-ß1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-ß1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.


Assuntos
Histonas/metabolismo , Lactatos/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Miofibroblastos/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Células Cultivadas , Humanos , Indóis/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/patologia , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Piridonas/farmacologia
14.
Expert Rev Respir Med ; 15(2): 239-247, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32981357

RESUMO

INTRODUCTION: Myofibroblasts are the primary executor and influencer in lung fibrosis. Latest studies on lung myofibroblast pathobiology have significantly advanced the understanding of the pathogenesis of lung fibrosis and shed new light on strategies targeting these cells to treat this disease. AREAS COVERED: This article reviewed the most recent progresses, mainly within the last 5 years, on the definition, origin, activity regulation, and targeting of lung myofibroblasts in lung fibrosis. We did a literature search on PubMed using the keywords below from the dates 2010 to 2020. EXPERT OPINION: With the improved cell lineage characterization and the advent of scRNA-seq, the field is having much better picture of the lung myofibroblast origin and mesenchymal heterogeneity. Additionally, cellular metabolism has emerged as a key regulation of lung myofibroblast pathogenic phenotype and is a promising therapeutic target for treating a variety of lung fibrotic disorders.


Assuntos
Miofibroblastos , Fibrose Pulmonar , Fibroblastos , Fibrose , Humanos , Pulmão/patologia
15.
Mol Ther ; 29(1): 347-364, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33007201

RESUMO

Follistatin-like 1 (FSTL1) is a matricellular protein that is upregulated during development and disease, including idiopathic pulmonary fibrosis (IPF), keloid, and arthritis. The profibrotic and pro-inflammatory roles of FSTL1 have been intensively studied during the last several years, as well as in this report. We screened and identified epitope-specific monoclonal neutralizing antibodies (nAbs) to functionally block FSTL1. FSTL1 nAbs attenuated bleomycin-induced pulmonary and dermal fibrosis in vivo and transforming growth factor (TGF)-ß1-induced dermal fibrosis ex vivo in human skin. In addition, FSTL1 nAbs significantly reduced existing lung fibrosis and skin fibrosis in experimental models. FSTL1 nAbs exerted their potent antifibrotic effects via reduced TGF-ß1 responsiveness and subsequent myofibroblast activation and extracellular matrix production. We also observed that FSTL1 nAbs attenuated the severity of collagen-induced arthritis in mice, which was accompanied by reduced inflammatory responses in vitro. Our findings suggest that FSTL1 nAbs are a promising new therapeutic strategy for the treatment of multiple organ fibrosis and systemic autoimmune diseases.


Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Biomarcadores , Suscetibilidade a Doenças , Proteínas Relacionadas à Folistatina/metabolismo , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Modelos Animais de Doenças , Descoberta de Drogas , Fibrose , Proteínas Relacionadas à Folistatina/antagonistas & inibidores , Proteínas Relacionadas à Folistatina/genética , Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Camundongos , Terapia de Alvo Molecular , Fator de Crescimento Transformador beta1/metabolismo
16.
BMJ Open ; 10(11): e036809, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177132

RESUMO

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterised by a fibrotic histological pattern found in usual interstitial pneumonia. Its causes, pathogenesis, clinical phenotype and molecular mechanisms are poorly defined. Large-scale, multicentre studies are warranted to better understand IPF as a disease in China, its associated risk factors, clinical characteristics, diagnosis, disease progression and treatment. METHODS AND ANALYSIS: The Idiopathic Pulmonary Fibrosis Registry China Study (PORTRAY) is a prospective, multicentre registry study of patients with IPF in China. Eight hundred patients will be enrolled over a 36-month period and followed for at least 3 years to generate a comprehensive database on baseline characteristics and various follow-up parameters including patient-reported outcomes. Biological specimens will also be collected from patients to develop a library of blood, bronchoalveolar lavage fluid and lung biopsy samples, to support future research. As of 15 December 2019, 204 patients from 19 large medical centres with relatively high IPF diagnosis and treatment rates had been enrolled. Patient characteristics will be presented using descriptive statistics. The Kaplan-Meier method will be used for survival analyses. Repeated measures will be used to compare longitudinal changes in lung function, imaging and laboratory tests. Results following analysis have been projected to be available by July 2025. ETHICS AND DISSEMINATION: The study protocol was reviewed and approved by the Institutional Review Board from all the study sites currently recruiting patients. Study results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03666234.


Assuntos
Fibrose Pulmonar Idiopática , Líquido da Lavagem Broncoalveolar , China/epidemiologia , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/epidemiologia , Estudos Prospectivos , Sistema de Registros
18.
Am J Respir Cell Mol Biol ; 63(4): 478-489, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32551949

RESUMO

Although endoplasmic reticulum (ER) unfolded protein response (UPRER) is well known, mitochondrial unfolded protein response (UPRmt) has not been recognized in alveolar epithelial cells. Furthermore, ER stress and mitochondrial dysfunction are frequently encountered in alveolar epithelial cells from an array of lung disorders. However, these two scenarios have been often regarded as separate mechanisms contributing to the pathogeneses. It is unclear whether there is interplay between these two phenomena or an integrator that couples these two signaling cascades in the stressed alveolar epithelial cells from those pathologies. In this study, we defined UPRmt in alveolar epithelial cells and identified ATF4 (activating transcription factor 4), but not ATF5, as the key regulator of UPRmt. We found that UPRER led to UPRmt and mitochondrial dysfunction in an ATF4-dependent manner. In contrast, mitochondrial stresses did not activate UPRER. We found that alveolar epithelial ATF4 and UPRmt were induced in aged mice with experimental pulmonary fibrosis as well as in patients with idiopathic pulmonary fibrosis. Finally, we found that the inducible expression of ATF4 in mouse alveolar epithelial cells aggravated pulmonary UPRmt, lung inflammation, body weight loss, and death upon bleomycin-induced lung injury. In conclusion, ER stress induces ATF4-dependent UPRmt and mitochondrial dysfunction, indicating a novel mechanism by which ER stress contributes to the pathogeneses of a variety of pulmonary disorders.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Células Epiteliais Alveolares/metabolismo , Mitocôndrias/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Células Epiteliais Alveolares/fisiologia , Animais , Apoptose/fisiologia , Linhagem Celular , Estresse do Retículo Endoplasmático/fisiologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Transdução de Sinais/fisiologia
19.
Int J Nanomedicine ; 15: 2269-2276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280219

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia. And, oxidation/antioxidant imbalance plays an important role in the progress of IPF. Fullerene is considered to be a novel "structural" antioxidant. This study aimed to explore if water-soluble C60 (C60(OH)22) can exhibit antifibrotic activity in its antioxidant role. METHODS: Healthy C57BL/6J mice were randomly grouped and induced pulmonary fibrosis by intratracheal injection of bleomycin. RESULTS: The survival rate of mice was observed and found that 10mg/kg was the optimal dose of water-soluble C60 for pulmonary fibrosis. We observed that water-soluble C60 can alleviate the severity of pulmonary fibrosis by observing the chest computed tomography, pulmonary pathology, and content of collagen, alpha smooth muscle actin and fibronectin in lung. Compared with bleomycin group, ROS, the content of TNF-α in BALF, and the number of fibroblasts was significantly decreased and the number of type Ⅱ alveolar epithelial cells was increased after treatment with C60. CONCLUSION: Therefore, thanks to its powerful antioxidant action, water-soluble C60 can reduce the severity of pulmonary fibrosis induced by bleomycin in mice.


Assuntos
Antioxidantes/farmacologia , Bleomicina/efeitos adversos , Fulerenos/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Colágeno , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fulerenos/administração & dosagem , Fulerenos/química , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Solubilidade , Água/química
20.
JCI Insight ; 5(5)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32027623

RESUMO

Recent studies have presented compelling evidence that it is not tissue-resident, but rather monocyte-derived alveolar macrophages (TR-AMs and Mo-AMs, respectively) that are essential to development of experimental lung fibrosis. However, whether apolipoprotein E (ApoE), which is produced abundantly by Mo-AMs in the lung, plays a role in the pathogenesis is unclear. In this study, we found that pulmonary ApoE was almost exclusively produced by Mo-AMs in mice with bleomycin-induced lung fibrosis. We showed that, although ApoE was not necessary for developing maximal fibrosis in bleomycin-injured lung, it was required for the resolution of this pathology. We found that ApoE directly bound to Collagen I and mediated Collagen I phagocytosis in vitro and in vivo, and this process was dependent on low-density lipoprotein receptor-related protein 1 (LPR1). Furthermore, interference of ApoE/LRP1 interaction impaired the resolution of lung fibrosis in bleomycin-treated WT mice. In contrast, supplementation of ApoE promoted this process in ApoE-/- animals. In conclusion, Mo-AM-derived ApoE is beneficial to the resolution of lung fibrosis, supporting the notion that Mo-AMs may have distinct functions in different phases of lung fibrogenesis. The findings also suggest a potentially novel therapeutic target for treating lung fibrosis, to which effective remedies remain scarce.


Assuntos
Apolipoproteínas E/metabolismo , Macrófagos Alveolares/metabolismo , Monócitos/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Apolipoproteínas E/genética , Bleomicina/toxicidade , Líquido da Lavagem Broncoalveolar , Colágeno Tipo I , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...