Mechanism of Huangqi Baihe Granules on Hypoxic Pulmonary Hypertension in Rats by Modulating the Inflammatory Response

OBJECTIVE To investigate the mechanism by which Huangqi Baihe Granules attenuate hypoxic pulmonary hypertension(HPH) in rats via modulation of inflammatory reactions.

METHODS Sixty male SD rats were randomly divided into 6 groups(n=10): the blank group, model group, dexamethasone group(5 mg·kg⁻¹), and Huangqi Baihe Granules high-, medium-, and low-dose(4.1, 2.05, and 1.025 g·kg⁻¹) groups. After 3 d of acclimatization, the blank and model groups received equal volumes of normal saline by gavage. The Huangqi Baihe Granules groups received continuous gavage for 14 d(once daily). The dexamethasone group received intraperitoneal injections for 3 days as a positive group before modeling(once daily). On the 15th day, all groups except the blank group were placed in a low-pressure simulation chamber for 14 d of continuous hypoxic exposure. At the end of the modeling period, right ventricular systolic pressure(RVSP) and right ventricular hypertrophy index(RVHI) were measured. Pathological changes in lung tissue were observed with HE staining. The vessel wall area/total vessel area(WA%) and wall thickness/external diameter(WT%) of small arteries in the lungs were calculated. Levels of tumor necrosis factor-α(TNF-α) and interleukin-1β(IL-1β) in bronchoalveolar lavage fluid(BALF) were detected. Transcriptomics was used to detect differentially expressed genes in lung tissues. Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) enrichment analyses were performed for these genes. qRT-PCR verified differential gene expression.

RESULTS  Compared with the blank group, rats in the model group showed significantly elevated RVSP and RVHI(P<0.01). HE staining showed obvious pathological damage in the lung tissue. There was thickening of the pulmonary vascular wall and narrowing of the lumen. Pulmonary vascular remodeling indicators, WT% and WA%, showed a significant increase(P<0.01). The levels of TNF-α and IL-1β in the BALF were also significantly increased(P<0.01). Compared with the model group, both the dexamethasone group and the high- and medium-dose groups of Huangqi Baihe Granules showed significant reductions in RVSP and RVHI(P<0.01). HE staining revealed improvements in the thickening of the small arterial walls and a reduction in lumen narrowing, resulting in reduced pathological damage to the pulmonary vasculature. WT% and WA% showed a significant decrease(P<0.01). Levels of TNF-α and IL-1β in BALF were also significantly reduced(P<0.01). Transcriptomic analysis identified 771 overlapping differentially expressed genes between the blank vs model comparison and the model vs high-dose comparison. The results of the GO enrichment analysis showed that most differentially expressed genes were associated with biological processes, while only a few were associated with cellular components or molecular functions. These genes were enriched in signaling pathways, such as the PI3K-AKT and NF-κB pathways, according to KEGG analysis. qRT-PCR results showed that the model group had significantly higher expression of PI3K, AKT, NF-κB, and IL-6 mRNA(P<0.01). Administration of Huangqi Baihe Granules reduced the expression of these genes(P<0.05, P<0.01).

CONCLUSION  Huangqi Baihe Granules may alleviate pathological progression in HPH rats by regulating the PI3K/AKT/NF-κB inflammatory pathway, suggesting their potential value as a therapeutic strategy for HPH.