Bufei Huoxue capsule (补肺活血胶囊) alleviates silicosis by inhibiting the activation of nucleotide-like receptor containing pyrin domain 3 inflammasome and macrophages polarization based on network pharmacology

doi:10.19852/j.cnki.jtcm.20240626.004

Journal of Traditional Chinese Medicine ›› 2024, Vol. 44 ›› Issue (6): 1236-1246.DOI: 10.19852/j.cnki.jtcm.20240626.004

• Research Articles • Previous Articles Next Articles

Bufei Huoxue capsule (补肺活血胶囊) alleviates silicosis by inhibiting the activation of nucleotide-like receptor containing pyrin domain 3 inflammasome and macrophages polarization based on network pharmacology

HANG Wenlu¹, WANG Lin¹, BO Yun², ZUO Shurun¹, WANG Songquan³, LI Haiquan¹, BU Chunlu¹, ZHAO Jie¹(), ZHOU Xianmei⁴()

1 Department of Respiratory and Critical Care Medicine, Second Afﬁliated Hospital of Xuzhou Medical University, Xuzhou 221000, China
2 Medical College of Anhui University of Science and Technology, Anhui 232001, China
3 School of Mechatronic Engineering, Jiangsu Normal University, Xuzhou 221000, China
4 Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210023, China

Received:2023-11-11 Accepted:2024-03-08 Online:2024-12-15 Published:2024-06-26
Contact: Prof. ZHOU Xianmei, Department of Respiratory Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210023, China. zhouxianmeijs@aliyun.com Telephone: +86-13813477830
Prof. ZHAO Jie, Department of Respiratory and Critical Care Medicine, Second Afﬁliated Hospital of Xuzhou Medical University, Xuzhou 221000, China.15005216612@163.com
Supported by:
Jiangsu Natural Science Foundation Youth Program: Regulation of Alveolar Macrophage Pyroptosis based on (Never in Mitosis Gene A)-Related Kinase 7 /Nucleotide-like Receptor Containing Pyrin Domain 3 Inflammasome to Explore the Mechanism of Bufei Huoxue Capsule on Pulmonary Fibrosis in Silicosis(BK20220236);Key Research and Development Project of Xuzhou City: Evaluation of Pyroptosis Induced by Nucleotide-like Receptor Containing Pyrin Domain 3 Inflammasome Activation in Pneumoconiosis Patients by Bronchoalveolar Lavage Fluid Ion Assay Combined with High-Resolution Computed Tomography Quantitative Analysis(KC22212);Youth Medical Science and Technology Innovation Project of Xuzhou Municipal Health Commission and Development Fund of Affiliated Hospital of Xuzhou Medical University: Study on the Regulation of Various Cytokines and the Effect of c-Jun Activation Domain-Binding Protein 1 on Immune Response in Lung Cancer(XWKYHT20210565);Youth Medical Science and Technology Innovation Project of Xuzhou Municipal Health Commission and Development Fund of Affiliated Hospital of Xuzhou Medical University: Study on the Regulation of Various Cytokines and the Effect of c-Jun Activation Domain-Binding Protein 1 on Immune Response in Lung Cancer(XYFY2020051)

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Abstract

Abstract:

OBJECTIVE: To predict the targets of Bufei Huoxue capsule (补肺活血胶囊, BFHX) using network pharmacology analysis and to explore its effects and functional targets in a silicotic rat model.

METHODS: The drug and disease targets were correlated through network pharmacology analysis to explore the targets and signaling pathways of BFHX affecting silicosis. NR8383 cells were cultured to verify the core genes and pathways. A rat model of silicosis was established to verify whether the mechanism behind SiO2-caused pulmonary fibrosis was alleviated by BFHX (0.82 g/kg) and how it affected key targets and pathways.

RESULTS: Overlapping BFHX and silicotic gene targets produced 159 interactive targets, and 55 were screened by network topology analysis. The results of gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses suggested that BFHX could affect silicosis through the nucleotide-like receptor containing pyrin domain 3 (NLRP3) inflammasome. In NR8383 cells, the expression of core genes related to the NLRP3 inflammasome could be inhibited by BFHX treatment. BFHX reduced the degree of alveolitis and collagen deposition, attenuating pulmonary fibrosis in SiO2-induced rat model. Pulmonary macrophage pyroptosis after SiO2 exposure was observed under transmission electron microscopy. BFHX alleviated the morphological characteristics of pyroptosis. BFHX also reduced the expression of NLRP3, caspase-1, interleukin-1 beta (IL-1β), IL-18, IL-6, and tumor necrosis factor-alpha in lung tissues of silicotic rat model. BFHX affected the K ion content in bronchoalveolar lavage fluid when assessed by energy dispersive spectrometer testing. The expression of CD68+ and CD206+ were also reduced after BFHX intervention.

CONCLUSION: NOD-like receptor signaling is vital for BFHX’s effects on silicosis. It exerts anti-pulmonary fibrosis effects by inhibiting pulmonary macrophage pyroptosis and polarization through NLRP3 inflammasome activation.

Key words: silicosis, pulmonary fibrosis, NLR proteins, inflammasomes, pyroptosis, Bufei Huoxue capsule

HANG Wenlu, WANG Lin, BO Yun, ZUO Shurun, WANG Songquan, LI Haiquan, BU Chunlu, ZHAO Jie, ZHOU Xianmei. Bufei Huoxue capsule (补肺活血胶囊) alleviates silicosis by inhibiting the activation of nucleotide-like receptor containing pyrin domain 3 inflammasome and macrophages polarization based on network pharmacology[J]. Journal of Traditional Chinese Medicine, 2024, 44(6): 1236-1246.

Figures/Tables 5

Figure 1 PPI network of 159 BFHX-silicosis common genes. PPI: protein-protein interaction; BFHX: Bufei Huoxue capsule.

Table 1 Core gene targets for silicosis treatment with Bufei Huoxue capsule

No.	Uniprot ID	Gene name	Protein target	Degree	Closeness centrality
1	P31749	AKT1	RAC-alpha serine/threonine-protein kinase	98	0.514815
2	P04637	TP53	Cellular tumor antigen p53	96	0.526515
3	P05412	JUN	Transcription factor Jun	96	0.53668
4	P01375	TNF	Tumor necrosis factor	86	0.5
5	P07900	HSP90AA1	Heat shock protein HSP 90-alpha	84	0.518657
6	P05231	IL6	Interleukin-6	80	0.5
7	P28482	MAPK1	Mitogen-activated protein kinase 1	72	0.496429
8	Q04206	RELA	Transcription factor p65	70	0.477663
9	P01106	MYC	Myc proto-oncogene protein	62	0.468013
10	P03372	ESR1	Estrogen receptor	60	0.466443
11	P01584	IL1B	Interleukin-1 beta	60	0.458746
12	Q16539	MAPK14	Mitogen-activated protein kinase 14	58	0.464883
13	P01100	FOS	Protein c-Fos	58	0.482639
14	P42224	STAT1	Signal transducer and activator of transcription 1-alpha/beta	52	0.468013
15	Q16665	HIF1A	Hypoxia-inducible factor 1-alpha	52	0.469595
16	P14780	MMP9	Matrix metalloproteinase-9	50	0.457237
17	P45983	MAPK8	Mitogen-activated protein kinase 8	50	0.451299
18	Q96EB6	SIRT1	NAD-dependent protein deacetylase sirtuin-1	48	0.448387
19	P10145	CXCL8	Interleukin-8	48	0.444089
20	P13500	CCL2	C-C motif chemokine 2	48	0.429012
21	P10275	AR	Androgen receptor	44	0.448387
22	P25963	NFKBIA	NF-kappa-B inhibitor alpha	44	0.448387
23	P37231	PPARG	Peroxisome proliferator-activated receptor gamma	44	0.454248
24	P22301	IL10	Interleukin-10	44	0.394886
25	P06400	RB1	Retinoblastoma-associated protein	42	0.435737
26	P60568	IL2	Interleukin-2	42	0.44127
27	P60484	PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	40	0.434375
28	P05112	IL4	Interleukin-4	40	0.41369
29	P17612	PRKACA	cAMP-dependent protein kinase catalytic subunit alpha	40	0.431677
30	P01579	IFNG	Interferon gamma	40	0.418675
31	P04626	ERBB2	Receptor tyrosine-protein kinase erbB-2	38	0.455738
32	Q03135	CAV1	Caveolin-1	38	0.445513
33	P08253	MMP2	72 kDa type IV collagenase	36	0.435737
34	Q13950	RUNX2	Runt-related transcription factor 2	36	0.434375
35	P01137	TGFB1	Transforming growth factor beta-1 proprotein	34	0.439873
36	P02741	CRP	C-reactive protein	34	0.380822
37	P24941	CDK2	Cyclin-dependent kinase 2	32	0.417417
38	P09601	HMOX1	Heme oxygenase 1	30	0.42638
39	P99999	CYCS	Cytochrome c	30	0.430341
40	P35228	NOS2	Nitric oxide synthase, inducible	30	0.430341
41	P05121	SERPINE1	Plasminogen activator inhibitor 1	30	0.374663
42	P19320	VCAM1	Vascular cell adhesion protein 1	30	0.379781
43	P02778	CXCL10	C-X-C motif chemokine 10	30	0.3687
44	P29474	NOS3	Nitric oxide synthase, endothelial	28	0.431677
45	P49841	GSK3B	Glycogen synthase kinase-3 beta	28	0.422492
46	P01583	IL1A	Interleukin-1 alpha	28	0.394886
47	Q07869	PPARA	Peroxisome proliferator-activated receptor alpha	28	0.457237
48	P31751	AKT2	RAC-beta serine/threonine-protein kinase	26	0.394886
49	P01375	TNF	Tumor necrosis factor	26	0.414925
50	Q14568	HSP90AA2	Heat shock protein HSP 90-alpha A2	24	0.410029
51	P13232	IL7	Interleukin-7	24	0.361039
52	P49137	MAPK2	MAP kinase-activated protein kinase 2	24	0.381868
53	Q04206	RELA	Transcription factor p65	24	0.402899

Table 1 Core gene targets for silicosis treatment with Bufei Huoxue capsule

No.	Uniprot ID	Gene name	Protein target	Degree	Closeness centrality
1	P31749	AKT1	RAC-alpha serine/threonine-protein kinase	98	0.514815
2	P04637	TP53	Cellular tumor antigen p53	96	0.526515
3	P05412	JUN	Transcription factor Jun	96	0.53668
4	P01375	TNF	Tumor necrosis factor	86	0.5
5	P07900	HSP90AA1	Heat shock protein HSP 90-alpha	84	0.518657
6	P05231	IL6	Interleukin-6	80	0.5
7	P28482	MAPK1	Mitogen-activated protein kinase 1	72	0.496429
8	Q04206	RELA	Transcription factor p65	70	0.477663
9	P01106	MYC	Myc proto-oncogene protein	62	0.468013
10	P03372	ESR1	Estrogen receptor	60	0.466443
11	P01584	IL1B	Interleukin-1 beta	60	0.458746
12	Q16539	MAPK14	Mitogen-activated protein kinase 14	58	0.464883
13	P01100	FOS	Protein c-Fos	58	0.482639
14	P42224	STAT1	Signal transducer and activator of transcription 1-alpha/beta	52	0.468013
15	Q16665	HIF1A	Hypoxia-inducible factor 1-alpha	52	0.469595
16	P14780	MMP9	Matrix metalloproteinase-9	50	0.457237
17	P45983	MAPK8	Mitogen-activated protein kinase 8	50	0.451299
18	Q96EB6	SIRT1	NAD-dependent protein deacetylase sirtuin-1	48	0.448387
19	P10145	CXCL8	Interleukin-8	48	0.444089
20	P13500	CCL2	C-C motif chemokine 2	48	0.429012
21	P10275	AR	Androgen receptor	44	0.448387
22	P25963	NFKBIA	NF-kappa-B inhibitor alpha	44	0.448387
23	P37231	PPARG	Peroxisome proliferator-activated receptor gamma	44	0.454248
24	P22301	IL10	Interleukin-10	44	0.394886
25	P06400	RB1	Retinoblastoma-associated protein	42	0.435737
26	P60568	IL2	Interleukin-2	42	0.44127
27	P60484	PTEN	Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN	40	0.434375
28	P05112	IL4	Interleukin-4	40	0.41369
29	P17612	PRKACA	cAMP-dependent protein kinase catalytic subunit alpha	40	0.431677
30	P01579	IFNG	Interferon gamma	40	0.418675
31	P04626	ERBB2	Receptor tyrosine-protein kinase erbB-2	38	0.455738
32	Q03135	CAV1	Caveolin-1	38	0.445513
33	P08253	MMP2	72 kDa type IV collagenase	36	0.435737
34	Q13950	RUNX2	Runt-related transcription factor 2	36	0.434375
35	P01137	TGFB1	Transforming growth factor beta-1 proprotein	34	0.439873
36	P02741	CRP	C-reactive protein	34	0.380822
37	P24941	CDK2	Cyclin-dependent kinase 2	32	0.417417
38	P09601	HMOX1	Heme oxygenase 1	30	0.42638
39	P99999	CYCS	Cytochrome c	30	0.430341
40	P35228	NOS2	Nitric oxide synthase, inducible	30	0.430341
41	P05121	SERPINE1	Plasminogen activator inhibitor 1	30	0.374663
42	P19320	VCAM1	Vascular cell adhesion protein 1	30	0.379781
43	P02778	CXCL10	C-X-C motif chemokine 10	30	0.3687
44	P29474	NOS3	Nitric oxide synthase, endothelial	28	0.431677
45	P49841	GSK3B	Glycogen synthase kinase-3 beta	28	0.422492
46	P01583	IL1A	Interleukin-1 alpha	28	0.394886
47	Q07869	PPARA	Peroxisome proliferator-activated receptor alpha	28	0.457237
48	P31751	AKT2	RAC-beta serine/threonine-protein kinase	26	0.394886
49	P01375	TNF	Tumor necrosis factor	26	0.414925
50	Q14568	HSP90AA2	Heat shock protein HSP 90-alpha A2	24	0.410029
51	P13232	IL7	Interleukin-7	24	0.361039
52	P49137	MAPK2	MAP kinase-activated protein kinase 2	24	0.381868
53	Q04206	RELA	Transcription factor p65	24	0.402899

Figure 2 KEGG pathway enrichment analysis for BFHX treatment of silicosis KEGG: kyoto encyclopedia of genes and genomes; BFHX: Bufei Huoxue capsule.

Figure 3 BFHX treatment reduced silicotic lung inflammation and fibrosis A: HE and Masson staining of lung tissues (× 20); A1-A5: HE staining; A1: control group; A2: model 28 d group; A3: BFHX 28 d group; A4: model 56 d group; A5: BFHX 56 d group; A6-10: Masson staining; A6: control group; A7: model 28 d group; A8: BFHX 28 d group; A9: model 56 d group; A10: BFHX 56 d group; B: immunohistochemical staining of TNF-α, IL-6 (× 20); B1-5: TNF-α staining; B1: control group; B2: model 28 d group; B3: BFHX 28 d group; B4: model 56 d group; B5: BFHX 56 d group; B6-10: IL-6 staining; B6: control group; B7: model 28 d group; B8: BFHX 28 d group; B9: model 56 d group; B10: BFHX 56 d group; C: analysis of TNF-α expression; D: analysis of IL-6 expression. Model group: modeling by SiO2 suspension of 50 mg/mL; BFHX group: modeling followed by drug treatment intragastrically at a daily dose of 0.82 g/kg. BFHX: Bufei Huoxue capsule; C: control; S: SiO2 exposure model group; TNF-α: tumor necrosis factor-alpha; IL-6: interleukin-6; IOD: integrated optical density; HE: hematoxylin and eosin. One?way analysis of variance was used to analyze the significance of differences between groups. The data were presented as the mean ± standard deviation (n = 6). aP < 0.01, compared with control group; bP < 0.01, compared with the SiO2 exposure group at the same time point; cP < 0.05, compared with control group; dP < 0.05, compared with the SiO2 exposure group at the same time point.

Figure 4 Immunofluorescence staining of NLRP3 signaling pathway in PMs A: double immunofluorescence staining for CD68+ and NLRP3 in lung tissues (× 20); A1, A2, A3: CD68+ staining; A4, A5, A6: NLRP3 staining; A7, A8, A9: DAPI staining; A10, A11, A12: merge of CD68+ and NLRP3 staining; A1, A4, A7, A10: control group; A2, A5, A8, A11: model group; A3, A6, A9, A12: BFHX group; B: double immunofluorescence staining for CD68+ and caspase-1 in lung tissues (× 20); B1, B2, B3: CD68+ staining; B4, B5, B6: caspase-1 staining; B7, B8, B9: DAPI staining; B10, B11, B12: merge of CD68+ and caspase-1 staining; B1, B4, B7, B10: control group; B2, B5, B8, B11: model group; B3, B6, B9, B12: BFHX group; C: double immunofluorescence staining for CD68+ and IL-1β in lung tissues (× 20); C1, C2, C3: CD68+ staining; C4, C5, C6: IL-1β staining; C7, C8, C9: DAPI staining; C10, C11, C12: merge of CD68+ and IL-1β staining; C1, C4, C7, C10: control group; C2, C5, C8, C11: model group; C3, C6, C9, C12: BFHX group; D: double immunofluorescence staining for CD68+ and IL-18 in lung tissues (× 20); D1, D2, D3: CD68+ staining; D4, D5, D6: IL-18 staining; D7, D8, D9: DAPI staining; D10, D11, D12: merge of CD68+ and IL-18 staining; D1, D4, D7, D10: control group; D2, D5, D8, D11: model group; D3, D6, D9, D12: BFHX group. Model group: 56 d of modeling by SiO2 suspension of 50 mg/mL (n = 3); BFHX group: 56 d of modeling followed by drug treatment intragastrically at a daily dose of 0.82 g/kg (n = 3). NLRP3: nucleotide-like receptor containing pyrin domain 3; PM: pulmonary macrophage; BFHX: Bufei Huoxue capsule; DAPI: 4',6-diamidino-2-phenylindole; IL-1β: interleukin-1β; IL-18: interleukin-18.

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Bufei Huoxue capsule (补肺活血胶囊) alleviates silicosis by inhibiting the activation of nucleotide-like receptor containing pyrin domain 3 inflammasome and macrophages polarization based on network pharmacology

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