Open Access

ARTICLE

Targeting c-Src/PKCα/MAPK/NF-κB: Salvianolic Acid A as a Protective Agent against Silica Nanoparticle-Induced Lung Inflammation

Yan-Jyun Lin^1,#, I-Ta Lee^2,#, Wen-Bin Wu^3,4, Chien-Chung Yang^5,6, Chiang-Wen Lee^7,8,9, Fuu-Jen Tsai^10,11,12, Hui-Ching Tseng¹³, Wei-Ning Lin⁴, Li-Der Hsiao⁴, Chuen-Mao Yang^4,*

1 Institute of Translational Medicine and New Drug Development, College of Medicine, China Medical University, Taichung, 40402, Taiwan
2 School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, 11031, Taiwan
3 School of Medicine, Fu Jen Catholic University, New Taipei City, 24205, Taiwan
4 Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, 24205, Taiwan
5 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, 33378, Taiwan
6 School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, 33302, Tawan
7 Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi, 61363, Taiwan
8 Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, 61363, Taiwan
9 Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi, 61363, Taiwan
10 School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan
11 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan
12 Division of Medical Genetics, China Medical University Children’s Hospital, Taichung, 40447, Taiwan
13 Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, 33303, Taiwan

* Corresponding Author: Chuen-Mao Yang. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: Cellular and Molecular Mechanisms Underlying Inflammation and Immune Regulation: From Genotoxicity to Apoptosis)

BIOCELL 2025, 49(7), 1265-1290. https://doi.org/10.32604/biocell.2025.066223

Received 01 April 2025; Accepted 17 June 2025; Issue published 25 July 2025

Abstract

Background: Silica nanoparticles (SiNPs), commonly utilized in industrial and biomedical fields, are known to provoke pulmonary inflammation by elevating cyclooxygenase-2 (COX-2) levels in human pulmonary alveolar epithelial cells (HPAEpiCs). Salvianolic acid A (SAA), a water-soluble polyphenol extracted from Salvia miltiorrhiza (Danshen), possesses well-documented antioxidant and anti-inflammatory activities. Nevertheless, its potential to counteract SiNP-induced inflammatory responses in the lung has not been thoroughly explored. Objective: This study aimed to evaluate the protective role and mechanistic actions of SAA against SiNP-triggered inflammation in both cellular and animal models. Methods: HPAEpiCs were pre-incubated with SAA prior to SiNP exposure to investigate changes in COX-2 expression and prostaglandin E₂ (PGE₂) secretion. A murine model of SiNP-induced lung inflammation was used for in vivo validation. Key inflammatory signaling proteins, including c-Src, PKCα, p42/p44 MAPK, and NF-κB p65, were analyzed for phosphorylation status. NF-κB promoter activity was also assessed. Pharmacological inhibitors and siRNA-mediated silencing were employed to verify the signaling cascade responsible for COX-2 regulation. Results: SAA treatment markedly suppressed SiNP-induced upregulation of COX-2 and PGE₂ in both HPAEpiCs and mouse lung tissues. SAA also reduced the activation (phosphorylation) of c-Src, PKCα, p42/p44 MAPK, and NF-κB p65, alongside diminishing NF-κB transcriptional activity. Functional studies using inhibitors and gene silencing further supported the involvement of these pathways in mediating the observed anti-inflammatory effect. Conclusion: By concurrently targeting several upstream pro-inflammatory signaling pathways, SAA demonstrates robust potential in alleviating SiNP-induced lung inflammation. These results highlight SAA as a promising candidate for therapeutic intervention in environmentally triggered respiratory conditions.

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