Network Pharmacology-Based Mechanistic Investigation of Jinshui Huanxian Formula Acting on Idiopathic Pulmonary Fibrosis.

Tiantian Liu,Shuishui Qi,Shaorui Ke,Pengli Xu,Jiansheng Li,Qin Hu,Peng Zhao,Arthur De Sá Ferreira

doi:10.1155/2021/8634705

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with high incidence, morbidity, and mortality rates. Jinshui Huanxian formula (JHF) is an empirical formula that targets the pathogenesis of lung-kidney qi deficiency and phlegm-blood stasis in pulmonary fibrosis (PF). The purpose of this study was to explore JHF's potential pharmacological mechanisms in IPF therapy using network intersection analysis. JHF's primary active components and corresponding target genes were predicted using various databases. Two sets of IPF disease genes were obtained from the DisGeNET and GEO databases and two sets of IPF drug targets were collected. The disease and drug target genes were analyzed. The JHF target genes that intersected with IPF's differentially expressed genes were identified to predict JHF's targets of action in IPF. The functions and pathways of predicted targets acting on IPF were analyzed using the DAVID and KEGG pathway databases. Finally, the resulting drug target mechanisms were validated in a rat model of PF. The initial analyses identified 494 active compounds and 1,304 corresponding targets for JHF. The intersection analysis revealed four common genes for the JHF targets, IPF disease, and anti-IPF drugs in the KEGG database. Furthermore, these genes were targeted by several JHF compounds. Seventy-two JHF targets were closely related to IPF, which suggests that they are therapeutically relevant. Target screening revealed that they regulate IPF through 18 pathways. The targets' molecular functions included regulation of oxidoreductase activity, kinase regulator activity, phosphotransferase activity, and transmembrane receptor protein kinase activity. In vivo experiments showed that JHF alleviated the degree of PF, including decreases in collagen deposition and epithelial-mesenchymal transition. This study systematically explored JHF's mechanisms to identify the specific target pathways involved in IPF. The generated pharmacological network, paired with in vivo validation, elucidates the potential roles and mechanisms of JHF in IPF therapy.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease, which is characterized by progressive fibrosis of lung parenchyma, resulting in function and respiratory failure
Fifty-four of the compounds revealed by the TCMSP and Traditional Chinese Medicines Integrated Database (TCMID) were duplicates, resulting in 494 unique compounds
IL6 and IL10 play an important role in the recruitment, activation, survival, and differentiation of fibroblasts into myofibroblasts in IPF [35, 36]

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease, which is characterized by progressive fibrosis of lung parenchyma, resulting in function and respiratory failure. It is the most common pulmonary interstitial disease with an estimated incidence of 2.8–9.3 cases per 100,000 person per year in Europe and North America [1]. Drugs commonly used to treat IPF include glucocorticoids, azathioprine, cyclosporin, warfarin, N-acetylcysteine, and acid suppressants. These drugs may induce adverse events (AEs), such as myelotoxicity associated with cytotoxic drugs or diffuse alveolar hemorrhage [3]. Compared to single-target drugs, multitarget drugs may be more effective due to synergistic effects or negative regulation of drug resistance [8, 9]

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