Baicalin inhibits inflammation of lipopolysaccharide-induced acute lung injury via toll like receptor-4/myeloid differentiation primary response 88/nuclear factor-kappa B signaling pathway

doi:10.19852/j.cnki.jtcm.20211214.004

Abstract

Abstract:

OBJECTIVE: To explore the effect and mechanism of baicalin in the treatment of acute lung injury (ALI) by in vivo and in vitro experiments.

METHODS: ALI was induced by instilling 10 mg/mL lipopolysaccharide (LPS) into the airway of rats. Different doses of baicalin (50 and 100 mg·kg ^–1·d^–1) were administered by gavage one day before modeling.

RESULTS: Baicalin significantly reduced the permeability of the alveolocapillary membrane, alleviated tissue injury and inflammatory infiltration, and inhibited the secretion of inflammatory factors and the infiltration of neutrophils. The decline in these inflammations was related to the inhibition of the toll like receptor-4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear factor-kappa B (NF-κB)/nod-like receptor pyrin containing 3 (NLRP3) signaling pathway and the mitogen-activated protein kinase (MAPK) signaling pathway.

CONCLUSIONS: Baicalin inhibits the secretion of inflammatory factors by inhibiting the TLR4-MyD88-NF-κB/NLRP3 pathway and the MAPK signaling pathway. Thus, it reduces lung bronchial epithelial layer, alveolar damage, and pulmonary edema as detected in the in vivo and in vitro experiments. Therefore, baicalin may be a potential preventive and therapeutic drug for ALI.

Key words: baicalin, acute lung injury, epithelial cells, lipopolysaccharides, inflammation

ZHU Changle, FENG Cuiling, FENG Feng, Yao Xiaoqin, WANG Guishu, SHI Liangtian, ZHENG Jiakun. Baicalin inhibits inflammation of lipopolysaccharide-induced acute lung injury via toll like receptor-4/myeloid differentiation primary response 88/nuclear factor-kappa B signaling pathway[J]. Journal of Traditional Chinese Medicine, 2022, 42(2): 200-212.

Figures/Tables 11

Table 1 RT-PCR primer sequences

Targeted gene	Forward primer and reverse primer
Human TLR4 F:	5'-TTTGGACAGTTTCCCACATTGA-3'
Human TLR4 R:	5'-AAGCATTCCCACCTTTGTTGG-3'
Human MyD88 F:	5'-GGCTGCTCTCAACATGCGA-3'
Human MyD88 R:	5'-CTGTGTCCGCACGTTCAAGA-3'
Human TRIF F:	5'-TGCCTATTCTGGAGCCGGTCAA-3'
Human TRIF R:	5'-AGTTGGAGTGGCGTCTGGTCTT-3'
Human NF-κB F:	5'-ACTGTAACTGCTGGACCCAAGGA-3'
Human NF-κB R:	5'-CGCCTCTGTCATTCGTGCTTCC-3'
Human GAPDH F:	5'-AGCCTTCTCCATGGTGGTGAAGAC-3'
Human GAPDH R:	5'-CGGAGTCAACGGATTTGGTCGTAT-3'

Table 2 Alterations in the permeability of the alveolocapillary membrane ($\bar{x}± s$)

Group	n	W/D lung weight ratio	Protein concentration (ng/μL)
Control	5	4.18±0.67^a	2.09±0.26^a
Model	5	9.61±0.72	5.34±0.05
L-baicalin	5	8.42±0.35^b	2.76±0.12^a
H-baicalin	5	5.67±0.49^a	2.67±0.04^a
CAM	5	5.99±0.55^a	2.51±0.10^a

Figure 1 Tissue injury and inflammatory infiltration L-baicalin: low-dose baicalin group, H-baicalin: high-dose baicalin group, CAM: Clarithromycin group, LPS: Model group, Lipopolysaccharide, NE: neutrophil. The rats in the low-dose baicalin (L-baicalin), high-dose baicalin (H-baicalin), and CAM groups were administered baicalin 50 mg·kg–1·d–1, baicalin 100 mg·kg–1·d–1, and CAM 45 mg·kg–1·d–1 by gavage, respectively, as described previously. The control and model groups were administered normal saline 0.1 mL·kg–1·d–1 by gavage. On the second day, the model and the drug groups were administered LPS 10 mg/mL (100 μL) by airway instillation. The number of neutrophils in control, LPS, L-baicalin, H-baicalin, and CAM groups. Count neutrophils in the high-power field (× 400) in at least ten random fields (n = 10); aP < 0.01 compared to the model group. The data were represented as mean ± standard deviation.

Table 3 Infiltration of inflammatory factors and MPO in BALF ($\bar{x}± s$)

Group	n	BALF-CXCL1 (pg/mL)	BALF-IL6 (pg/mL)	BALF-IL-1β (pg/mL)	BALF-TNF-α (pg/mL)	BALF-MPO (U/L)
Control	6	33.8±2.1^a	39.8±17.7^a	6.8±1.4^b	62.8±5.0^a	113.1±8.5^a
Model	6	47.4±4.6	309.6±25.1	10.8±0.9	116.1±9.3	181.5±14.5
L-baicalin	6	40.7±5.5^b	294.2±21.5	10.3±0.8	93.2±9.7^a	140.6±14.3^a
H-baicalin	6	23.9±2.0^a	166.6±28.3^a	5.5±0.3^b	58.1±5.5^a	111.6±4.2^a
CAM	6	19.6±0.8^a	148.0±37.3^a	3.3±0.2^a	46.1±2.3^a	65.2±8.2^a

Table 4 Secretion of inflammatory cytokines and MPO in the serum ($\bar{x}± s$)

Group	n	serum-CXCL1 (pg/mL)	serum -IL6 (pg/mL)	serum -IL-1β (pg/mL)	serum-TNF-α (pg/mL)	Serum-MPO (U/L)
Control	5	27.0±2.5^a	17.3±2.4^a	5.8±0.5^a	71.5±4.8^a	107.8±13.4^a
Model	5	41.2±3.8	61.7±3.7	10.5±1.6	101.4±5.7	162.9±13.3
L-baicalin	5	36.3±3.8^b	56.7±4.0	8.7±0.7^b	96.4±7.3	121.7±8.7^a
H-baicalin	5	20.9±1.8^a	41.1±1.6^a	4.5±0.8^a	53.1±7.6^a	91.4±8.7^a
CAM	5	16.5±1.0^a	36.9±1.2^a	2.5±0.4^a	38.8±3.7^a	62.3±6.0^a

Figure 2 Effects of baicalin on inhibiting the protein expression of TLR4-TRIF/MyD88-NF-κB pathway signaling and NLRP3 in lung tissues detected by Western blotting A-E: expression of TLR4, TRIF, MyD88, NLRP3, and p-NF-κB proteins of control group, LPS group, baicalin group, CAM group in lung tissues from rats detected by WB. L-baicalin: low-dose baicalin group, H-baicalin: high-dose baicalin group, CAM: Clarithromycin group, LPS: model group, lipopolysaccharide. The rats in the low-dose baicalin (L-baicalin), high-dose baicalin (H-baicalin), and CAM groups were administered baicalin 50 mg·kg–1·d–1, baicalin 100 mg·kg–1·d–1, and CAM 45 mg·kg–1·d–1 by gavage, respectively, as described previously. The control and model groups were administered normal saline 0.1 mL·kg–1·d–1 by gavage. On the second day, the model and the drug groups were administered LPS 10 mg/mL (100 μL) by airway instillation. TLR4: toll-like receptor 4; TRIF: toll-receptor-associated activator of interferon; MyD88: myeloid differentiation factor 88; p-NF-κB: phospho-nuclear factor-kappa B; NLRP3: nod-like receptor pyrin containing 3. aP < 0.05, bP < 0.01, compared to the model group (n = 5) for each group. The data were represented as mean ± standard deviation.

Figure 3 Effects of baicalin on inhibiting the expression of TLR4-TRIF/MyD88-NF-κB pathway and NLRP3 protein in lung tissues detected by immune-ohistochemistry analysis A-D: expression of TLR4, MyD88, p-NF-κB, and NLRP3 proteins in the control group, LPS group, baicalin group, and CAM group in lung tissues from rats detected by immunohistochemistry. L-baicalin: low-dose baicalin group, H-baicalin: high-dose baicalin group, CAM: Clarithromycin group, LPS: Model group, Lipopolysaccharide. The rats in the low-dose baicalin (L-baicalin), high-dose baicalin (H-baicalin), and CAM groups were administered baicalin 50 mg·kg–1·d–1, baicalin 100 mg·kg–1·d–1, and CAM 45 mg·kg–1·d–1 by gavage, respectively, as described previously. The control and model groups were administered normal saline 0.1 mL·kg–1·d–1 by gavage. On the second day, the model and the drug groups were administered LPS 10 mg/mL (100 μL) by airway instillation. TLR4: toll-like receptor 4; TRIF: toll-receptor-associated activator of interferon; MyD88: myeloid differentiation factor 88; p-NF-κB: phospho-nuclear factor-kappa B; NLRP3: nod-like receptor pyrin containing 3. aP < 0.05, bP < 0.01, compared to the model group (n = 5) for each group. The data were represented as mean ± standard deviation.

Figure 4 Effects of baicalin on inhibiting MAPK pathway protein expression in lung tissues detected by Western blotting A-B: expression of p-ERK (Phospho-p44/42 Mitogen-activated protein kinase) and p-P38 (Phospho-p38 Mitogen-activated protein kinase) in lung tissues from rats detected by WB. L-baicalin: low-dose baicalin group, H-baicalin: high-dose baicalin group, CAM: clarithromycin group, LPS: model group, lipopolysaccharide. MAPK pathway: mitogen-activated protein kinase pathway. The rats in the low-dose baicalin (L-baicalin), high-dose baicalin (H-baicalin), and CAM groups were administered baicalin 50 mg·kg–1·d–1, baicalin 100 mg·kg–1·d–1, and CAM 45 mg·kg–1·d–1 by gavage, respectively, as described previously. The control and model groups were administered normal saline 0.1 mL·kg–1·d–1 by gavage. On the second day, the model and the drug groups were administered LPS 10 mg/mL (100 μL) by airway instillation. In A and B, aP < 0.05, bP < 0.01, compared to the model group (n = 5) for each group. The data were represented as mean ± standard deviation.

Figure 5 Effects of baicalin on inhibiting MAPK pathway protein expression in lung tissues detected by immunohistochemical A, B: protein expression of p-ERK (phospho-p44/42 Mitogen-activated protein kinase) and p-P38 (phospho-p38 Mitogen-activated protein kinase) in lung tissues from rats detected by immunohistochemistry. L-baicalin: low-dose baicalin group, H-baicalin: high-dose baicalin group, CAM: Clarithromycin group, LPS: model group, lipopolysaccharide. MAPK pathway: Mitogen-activated protein kinase pathway. The rats in the low-dose baicalin (L-baicalin), high-dose baicalin (H-baicalin), and CAM groups were administered baicalin 50 mg·kg–1·d–1, baicalin 100 mg·kg–1·d–1, and CAM 45 mg·kg–1·d–1 by gavage, respectively, as described previously. The control and model groups were administered normal saline 0.1 mL·kg–1·d–1 by gavage. On the second day, the model and the drug groups were administered LPS 10 mg/mL (100 μL) by airway instillation. aP < 0.01 compared to the model group (n = 5) for each group. The data were represented as mean ± standard deviation.

Figure 6 Effects of baicalin on inhibiting TLR4-TRIF/MyD88-NF-κB/NLRP3 pathway protein expression in epithelial cells A-E: expression of TLR4, TRIF, MyD88, p-NF-κB, and NLRP3 proteins in the epithelial cells in the control group, LPS group, L-baicalin group, H-baicalin group, and CAM group. Control: epithelial cells cultured with BEGM for 48 h. LPS: model group, epithelial cells treated with LPS (lipopolysaccharide) 50 μg/mL for 48 h. L-baicalin: low-dose baicalin group, epithelial cells treated with LPS 50 μg/mL for 48 h and baicalin 5 μg/mL for 24 h. H-baicalin: high-dose baicalin group, epithelial cells treated with LPS 50 μg/mL for 48 h and baicalin 10 μg/mL for 24 h. CAM: Clarithromycin group, epithelial cells treated with LPS 50 μg/mL for 48 h and CAM 10 μg/mL for 24 h. TLR4: toll like receptor-4; TRIF: toll-receptor-associated activator of interferon; MyD88: myeloid differentiation factor 88; p-NF-κB: phospho-nuclear factor-kappa B; NLRP3: Nod-like receptor pyrin containing 3. aP < 0.05, bP < 0.01, compared to the model group (n = 4 for each group). The data were represented as mean ± standard deviation.

Table 5 Effects of baicalin on inhibiting TLR4-MyD88-NF-κB pathway mRNA expression in LPS-induced epithelial cells ($\bar{x}± s$)

Group	n	TLR4 mRNA	TRIF mRNA	MYD88 mRNA	NF-ΚB mRNA
Control	5	0.76±0.18^a	0.56±0.10^a	1.72±0.24^a	4.36±0.77^a
Model	5	3.45±0.36	3.84±0.45	6.20±0.74	1.06±0.21
L-baicalin	5	2.49±0.37^b	3.73±0.40	5.82±0.31	1.74±0.42^b
H-baicalin	5	2.32±0.27^a	3.62±0.26	3.95±0.30^a	3.01±0.24^a
CAM	5	1.06±0.18^a	3.08±0.23^b	4.88±0.25^b	2.55±0.23^a

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