Prevention of pulmonary fibrosis with salvianolic acid a by inducing fibroblast cell cycle arrest and promoting apoptosis

Yongming Pan; Huiying Fu; Qing Kong; Yin Xiao; Qiyang Shou; Hongqiang Chen; Yuehai Ke; Minli Chen

doi:10.1016/j.jep.2014.07.049

Prevention of pulmonary fibrosis with salvianolic acid a by inducing fibroblast cell cycle arrest and promoting apoptosis

J Ethnopharmacol. 2014 Sep 29;155(3):1589-96. doi: 10.1016/j.jep.2014.07.049. Epub 2014 Aug 4.

Authors

Yongming Pan¹, Huiying Fu², Qing Kong¹, Yin Xiao¹, Qiyang Shou¹, Hongqiang Chen³, Yuehai Ke³, Minli Chen⁴

Affiliations

¹ Experimental Animal Research Center, Zhejiang Chinese Medical University, Hangzhou 310053, China.
² Center Laboratory, Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China.
³ Program in Molecular Cell Biology, Department of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ Experimental Animal Research Center, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: cmli991@aliyun.com.

PMID: 25102244
DOI: 10.1016/j.jep.2014.07.049

Abstract

Ethnopharmacological relevance: Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine (TCM), often in combination with other herbs, to treat a diversity of ailments. More recent studies have focused on its possible roles in the treatment of respiratory diseases (pneumonia and pulmonary fibrosis) and found that it has pharmacological activity that protects pulmonary morphology and function. However, the mechanism underlying this activity has not yet been clarified.

Materials and methods: The purpose of this study was to investigate the anti-pulmonary fibrosis effects exerted by salvianolic acid A (SAA), the ingredient responsible for the pharmacological activity of Danshen, and the underlying mechanisms. Bleomycin (BLM)-induced rat pulmonary fibrosis was used to evaluate the antifibrotic role of SAA, and fibroblast cells were used to study the mechanism involved.

Results: BLM-treated rats exhibited increased alveolar wall thickness and collagen deposition in lung tissues, but these pathologies were greatly attenuated by daily administration of SAA. We also found that SAA significantly inhibited the proliferation, adhesion and migration of fibroblasts in vitro. This was partly due to a strong induction of cell cycle arrest and apoptosis upon SAA treatment. Consistent with these phenotypes, we observed decreased expression of the cell cycle-related proteins cyclin D1, cyclin E1, and cyclin B1, and increased expression of p53 and p21 in SAA-treated cells. In addition, the anti-apoptotic Bcl-2 protein decreased in a dose-dependent manner, while cleaved caspase-3 protein increased upon SAA treatment.

Conclusions: These results suggest that the alleviation of rat pulmonary fibrosis by SAA is due to the inhibition of fibroblast proliferation and induction of apoptosis, which occurs mainly through p53-dependent growth arrest and apoptosis. We suggest that SAA should be considered as a potential novel therapeutic agent for the treatment of fibrotic lung diseases.

Keywords: Apoptosis; Cell cycle; Phenotypic modulation; Pulmonary fibrosis; Salvianolic acid A.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Bleomycin
Caffeic Acids / pharmacology*
Caffeic Acids / therapeutic use*
Cell Adhesion / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line
Cell Movement / drug effects
Fibroblasts / cytology
Fibroblasts / drug effects*
Fibroblasts / physiology
Lactates / pharmacology*
Lactates / therapeutic use*
Male
Mice
Pulmonary Fibrosis / chemically induced
Pulmonary Fibrosis / drug therapy*
Rats, Wistar

Substances

Caffeic Acids
Lactates
Bleomycin
salvianolic acid A