RESUMO
Silicosis caused by inhalation of silica particles leads to more than ten thousand new occupational exposure-related deaths yearly. Exacerbating this issue, there are currently few drugs reported to effectively treat silicosis. Tetrandrine is the only drug approved for silicosis treatment in China, and despite more than decades of use, its efficacy and mechanisms of action remain largely unknown. Here, in this study, we established silicosis mouse models to investigate the effectiveness of tetrandrine of early and late therapeutic administration. To this end, we used multiple cardiopulmonary function test, as well as markers for inflammation and fibrosis. Moreover, using single cell RNA sequencing and transcriptomics of lung tissue and quantitative microarray analysis of serum from silicosis and control mice, our results provide a novel description of the target pathways for tetrandrine. Specifically, we found that tetrandrine attenuated silicosis by inhibiting both the canonical and non-canonical NLRP3 inflammasome pathways in lung macrophages. Taken together, our work showed that tetrandrine yielded promising results against silicosis-associated inflammation and fibrosis and further lied the groundwork for understanding its molecular targets. Our results also facilitated the wider adoption and development of tetrandirne, potentially accelerating a globally accepted therapeutic strategy for silicosis.
Assuntos
Inflamassomos , Silicose , Animais , Benzilisoquinolinas , Fibrose , Inflamassomos/metabolismo , Inflamação/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Silicose/tratamento farmacológico , Silicose/metabolismoRESUMO
Silicosis is a global occupational disease characterized by lung dysfunction, pulmonary inflammation, and fibrosis, for which there is a lack of effective drugs. Pirfenidone has been shown to exert anti-inflammatory and anti-fibrotic properties in the lung. However, whether and how pirfenidone is effective against silicosis remains unknown. Here, we evaluated the efficacy of pirfenidone in the treatment of early and advanced silicosis in an experimental mouse model and explored its potential pharmacological mechanisms. We found that pirfenidone alleviated silica-induced lung dysfunction, secretion of inflammatory cytokines (TNF-α, IL-1ß, IL-6) and deposition of fibrotic proteins (collagen I and fibronectin) in both early and advanced silicosis models. Moreover, we observed that both 100 and 200 mg/kg pirfenidone can effectively treat early-stage silicosis, while 400 mg/kg was recommended for advanced silicosis. Mechanistically, antibody array and bioinformatic analysis showed that the pathways related to IL-17 secretion, including JAK-STAT pathway, Th17 differentiation, and IL-17 pathway, might be involved in the treatment of silicosis by pirfenidone. Further in vivo experiments confirmed that pirfenidone reduced the production of IL-17A induced by silica exposure via inhibiting STAT3 phosphorylation. Neutralizing IL-17A by anti-IL-17A antibody improved lung function and reduced pulmonary inflammation and fibrosis in silicosis animals. Collectively, our study has demonstrated that pirfenidone effectively ameliorated silica-induced lung dysfunction, pulmonary inflammation and fibrosis in mouse models by inhibiting the secretion of IL-17A.
Assuntos
Interleucina-17 , Pneumonia , Animais , Modelos Animais de Doenças , Fibrose , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-17/metabolismo , Janus Quinases/metabolismo , Janus Quinases/uso terapêutico , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Piridonas , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição STAT/uso terapêutico , Transdução de Sinais , Dióxido de Silício/toxicidadeRESUMO
ABSTRACT: Pneumoconiosis refers to a spectrum of pulmonary diseases caused by inhalation of mineral dust, usually as the result of certain occupations. The main pathological features include chronic pulmonary inflammation and progressive pulmonary fibrosis, which can eventually lead to death caused by respiratory and/or heart failure. Pneumoconiosis is widespread globally, seriously threatening global public health. Its high incidence and mortality lie in improper occupational protection, and in the lack of early diagnostic methods and effective treatments. This article reviews the epidemiology, safeguard procedures, diagnosis, and treatment of pneumoconiosis, and summarizes recent research advances and future research prospects.
Assuntos
Doenças Profissionais , Exposição Ocupacional , Pneumoconiose , Fibrose Pulmonar , Poeira , Humanos , Pneumoconiose/diagnóstico , Pneumoconiose/epidemiologiaRESUMO
AIMS: Gastric hyperplastic polyps (GHPs) are the most common polypoid lesion of the stomach, and their malignant potential has been demonstrated. In the present study, we evaluated the mucin phenotypes of GHPs and investigated the relationships among mucin phenotypes and clinical-pathological factors, proliferative activity and p53 expression in GHPs. METHODS: The CD10, MUC2, MUC5AC and MUC6 expression patterns of 238 GHPs were examined by immunohistochemical staining. The GHP mucin phenotypes were divided into 4 subtypes: the gastric mucin phenotype (G-type), the intestinal mucin phenotype (I-type), the mixed or gastrointestinal mucin phenotype (GI-type) and the unclassified mucin phenotype (U-type). RESULTS: The G and GI types were observed in 58% and 42% of the GHPs, respectively. However, no I or U type GHPs were found in the present study. The GI type was more common in lesions with dysplasia or carcinoma than in polyps without dysplasia or carcinoma (P<0.001). P53-positivity rate and high index of Ki-67 tumors were significantly more common in the GI-type than in the G-type polyps (P<0.001). CONCLUSIONS: The mucin phenotype may serve as a useful marker for the malignant potential of GHPs, and GI-type GHPs should be considered to be a lesion with malignant potential.