Tetrandrine alleviates silicosis by inhibiting canonical and non-canonical NLRP3 inflammasome activation in lung macrophages.

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.

Pirfenidone ameliorates silica-induced lung inflammation and fibrosis in mice by inhibiting the secretion of interleukin-17A.

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.

The Potential Diagnostic Biomarkers for the IgG Subclass in Coal Workers' Pneumoconiosis.

Evidence suggests that exposure to coal dust increases immunoglobulin concentration. However, there is a paucity of data reporting immunoglobulin G (IgG) subclass in coal workers' pneumoconiosis (CWP). Therefore, this study intended to evaluate potential diagnostic biomarkers for the disease. CWP patients, dust-exposed workers without pneumoconiosis (DEW), and matched healthy controls (HCs) presented to the General Hospital of Datong Coal Mining Group and Occupational Disease Prevention and Treatment Hospital of Datong Coal Mining Group between May 2019 and September 2019 were recruited. The serum immunoglobulin concentration was determined by the multiplex immunoassay technique. Totally, 104 CWP patients, 109 DEWs, and 74 HCs were enrolled. Serum levels of IgG1, IgG2, IgM, and IgA were elevated in CWPs compared with those in DEWs and HCs (P < 0.05). The order of diagnostic accuracy between CWPs and DEWs depicted by the receiver operating characteristic (ROC) curve was IgG2, IgM, IgG1, IgG3, and IgA. Significantly higher IgG1/IgG3 and IgG2/IgG3 ratios were observed in the CWP group than in DEW and HC groups. Based on the IgG2/IgG3 ratio, the area under the ROC curve between CWP and DEW was 0.785 (95% CI 0.723-0.838), with a sensitivity of 73.1% and a specificity of 73.4%. Our findings suggest that IgG1, IgG2, IgM, and IgA are higher in the CWPs than DEWs and HCs. The IgG2/IgG3 ratio provides a viable alternative for the diagnosis of CWP.

[Clinical observation of home noninvasive positive pressure ventilation in hypercapnic patient with stable severe chronic obstructive pulmonary disease].

OBJECTIVE: To evaluate the efficacy and safety of home noninvasive positive pressure ventilation (HNIPPV) in hypercapnic patients with stable severe chronic obstructive pulmonary disease (COPD). METHODS: Forty four patients (30 males and 14 females, mean age 68.5 years (range: 60 - 80)) were recruited from a total of 106 patients with arterial PaCO2 ≥ 55 mm Hg in Second Hospital Affiliated to Harbin Medical University from January 2009 to December 2010. Their clinical data were collected and analyzed. The patients in the HNIPPV group (n = 20) accepted tiotropium bromide, doxofylline tablets and HNIPPV treatment while those in the control group (n = 24) tiotropium bromide, doxofylline tablets and a low-flow inhalation of oxygen. The entire observation period was 6 months. The parameters before and after 6-month follow-up were compared, including lung function test, 6-min walking distance (6MWD), arterial blood gases (PaO2 and PaCO2), dyspnea grade, scores of emotional disorders and mean pulmonary artery pressure (mPAP). RESULTS: No significant difference existed in the baseline data between the HNIPPV and control groups. The forced expiratory volume in one second (FEV(1)), forced vital capacity (FVC), inspiratory capacity (IC), 6MWD, PaO2, PaCO2, dyspnea grade, hospitalization rate, anxiety scores, depression scores and mPAP showed no significant difference between the HNIPPV and control groups before treatment. However, at Month 6, the differences of IC, 6MWD, PaO2, PaCO2, dyspnea grade, anxiety scores, depression scores and mPAP in HNIPPV group ((1.80 ± 0.14) L, (266 ± 24) m, (62.6 ± 4.6) mm Hg, (46.8 ± 2.2) mm Hg, (2.2 ± 0.5), (6.5 ± 2.4), (6.0 ± 1.6), (33.8 ± 2.4) mm Hg) were statistically significant compared with the control group ((1.62 ± 0.14) L, (194 ± 23) m, (56.2 ± 3.8) mm Hg, (55.6 ± 3.0) mm Hg, (3.2 ± 0.6), (10.6 ± 2.8), (10.2 ± 2.4), (36.6 ± 2.4) mm Hg) (P values: 0.031, 0.018, 0.025, 0.026, 0.001, 0.013, 0.002, 0.014 respectively). FEV(1) and FVC in the HNIPPV group improved slightly but with no statistically significant difference (all P > 0.05). Two patients in the control group were taken to hospital because of acute exacerbation. And hospitalization rates increased in the control group. But no statistically significant difference existed between the HNIPPV and control groups (P > 0.05). The tolerance and compliance of HNIPPV in the HNIPPV group were better and the patients in the HNIPPV group had no pulmonary barotraumas. CONCLUSION: HNIPPV plus tiotropium bromide and doxofylline tablets is both effective and safe in the treatment of hypercapnic patient with stable severe COPD.

[The effect of marrow mesenchymal stem cell transplantation on pulmonary fibrosis in rats].

OBJECTIVE: To study the possible mechanisms of marrow mesenchymal stem cells (MSC) in therapy of bleomycin (BLM)-induced pulmonary fibrosis in rats. METHODS: Fifty-four female Wistar rats were randomly divided into a control group, a BLM group and a MSC group. The control group received intratracheal normal saline, the BLM group received intratracheal instillation of bleomycin, and the MSC group was injected with male rat MSC solution of 0.5 ml (2.5×10(6) cells) via the tail vein after intratracheal instillation of bleomycin. Six rats from each group were killed on day 7, 14 and 28 of the experiments. BrdU labeling rate was measured before MSC transplantation. Lung tissue specimens were obtained for pathological examination, hydroxyproline content measurement, and detection of the expression of type II alveolar cell (ATII) specific marker-pulmonary surfactant protein-C (SP-C) in BrdU labeled MSC using dual immunofluorescence method. RT-PCR method was used to detect SP-C mRNA expression in the lung tissue and the bone marrow at different stages. The bone marrow mobilization involved in repair of type II alveolar cells after lung injury was observed. RESULTS: The final concentration of BrdU labeled MSC at 48 h was 10 µmol/L, while the labeling efficiency was>98%, and the passage cells could be continuously labeled. In the MSC group, BrdU labeled MSCs with expression of SP-C were observed in all frozen sections of lung tissue at day 7, 14, and 28. By day 28, the lung fibrosis scores of the MSC group and the BLM group were (2.17 ± 0.26) and (2.83 ± 0.24), respectively, the lung tissue hydroxyproline contents were (138 ± 21) mg/g and (184 ± 19) mg/g, respectively, and the lung tissue SP-C mRNA expressions were (0.98 ± 0.15) and (0.59 ± 0.14), respectively. For both groups the SP-C mRNA expressions in the bone marrow at different stages were significantly increased as compared to the control group. CONCLUSIONS: Marrow mesenchymal stem cells could be transplanted into lung tissues of rats, and transformed into type II alveolar cells and was shown to prevent the development of pulmonary fibrosis. The damage-induced enhancement of host bone marrow mobilization was also involved in the repair process.

Comparative study on WHO Western Pacific region and World Federation of Chinese Medicine Societies international standard terminologies on traditional medicine: syndrome differentiation of combined visceral diseases.

Yi Guan Jian decoction is a traditional Chinese medicine formula noted in Wei Yu-huang's Xu Ming Yi Lei An (Supplement to the Classified Medical Records of Famous Physicians). Acne vulgaris and chronic pelvic inflammation could be successfully treated by the decoction following the principle of formula corresponding to syndromes. The identical characteristics of constitution are found among the patients treated by the decoction, known as the "Yi Guan Jian constitution". It indicates that patients can be treated according to the constitutional characteristics.