Abstract
BackgroundAs a prevalent type of cryptogenic fibrotic disease with high mortality, idiopathic pulmonary fibrosis (IPF) still lacks effective therapeutic drugs. The compounds extracted from buds and flowers of Chrysanthemum indicum Linné with supercritical-carbon dioxide fluid (CISCFE) has been confirmed to have antioxidant, anti-inflammatory, and lung-protective effects. This paper aimed to clarify whether CISCFE could treat IPF induced by bleomycin (BLM) and elucidate the related mechanisms.MethodsRats (Sprague-Dawley, male) were separated into the following groups: normal, model, pirfenidone (50 mg/kg), CISCFE-L, −M, and -H (240, 360, and 480 mg/kg/d, i.g., respectively, for 4 weeks). Rats were given BLM (5 mg/kg) via intratracheal installation to establish the IPF model. A549 and MRC-5 cells were stimulated by Wnt-1 to establish a cell model and then treated with CISCFE. Haematoxylin-eosin (H&E) and Masson staining were employed to observe lesions in the lung tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were performed to observe changes in genes and proteins connected with the Wnt/β-catenin pathway.ResultsCISCFE inhibited the proliferation of MRC-5 cells (IC50: 2.723 ± 0.488 μg/mL) and A549 cells (IC50: 2.235 ± 0.229 μg/mL). In rats, A549 cells, and MRC-5 cells, BLM and Wnt-1 obviously induced the protein expression of α-smooth muscle actin (α-SMA), vimentin, type I collagen (collagen-I), and Nu-β-catenin. The mRNA levels of matrix metalloproteinase-3 (MMP-3) and − 9 (MMP-9), two enzymes that degrade and reshape the extracellular matrix (ECM) were also increased while those of tissue inhibitor of metalloproteinase 1 (TIMP-1) were decreased. However, CISCFE reversed the effects of BLM and Wnt-1 on the expression pattern of these proteins and genes.ConclusionThese findings showed that CISCFE could inhibit IPF development by activating the Wnt/β-catenin pathway and may serve as a treatment for IPF after further investigation.
Highlights
As a prevalent type of cryptogenic fibrotic disease with high mortality, idiopathic pulmonary fibrosis (IPF) still lacks effective therapeutic drugs
Effects of Wnt‐1 and CISCFE on MRC‐5 and A549 cells Figure 1 shows that the growth rates of A549 (1A) and MRC-5 cells (1B) were obviously faster after cells were treated with Wnt-1 (5, 10, 15, 20, 30, 40, 60, and 100 ng/mL)
C ISCFE significantly inhibited the proliferation of A549 cells (IC50: 2.723 ± 0.488 μg/mL) (1C) and MRC-5 cells (IC50: 2.236 ± 0.230 μg/mL) (1D)
Summary
As a prevalent type of cryptogenic fibrotic disease with high mortality, idiopathic pulmonary fibrosis (IPF) still lacks effective therapeutic drugs. Idiopathic pulmonary fibrosis (IPF), a prevalent fibrotic disease with high mortality, is a complex pathology of the lung with unknown aetiology [1, 2]. Excess inflammation and abnormal repair result in epithelial-mesenchymal transition (EMT) [4] and abnormal growth of lung interstitial cells, resulting in changes in the collagens deposed into the extracellular matrix (ECM) [5]. As IPF is a pulmonary disease characterized by progressive interstitial fibrosis, parenchymal inflammation and accumulation of ECM protein [6], the detailed cellular and molecular mechanisms of its development remain unknown. The main treatment strategies of IPF include glucocorticoids, antifibrinolytic agents, and antioxidants. New potential targets and agents to ameliorate IPF urgently need to be identified and developed
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