Pirfenidone is mainly used in treatment for idiopathic pulmonary fibrosis based on its inhibition on production of growth factors, such as TGFβ. Over-expression of TGF-β in chronic inflammation, remodeling, fibrotic process and susceptibility to viral infection is established in the most prevalent chronic respiratory diseases including idiopathic pulmonary fibrosis, lung cancer, chronic obstructive pulmonary disease and asthma[1]. Pirfenidone can inhibit TGFβ expression or TGFβ-induced fibrogenesis by blocking nuclear translocation of Smads[2]. Treatment of pirfenidone at concentration of 0.3 mg/ml can decrease the expression level of TGF-β1, 2, 3 in HTF cells[2]. Pretreatment with pirfenidone at concentration 0.5 mg/ml for 1h can inhibit TGFβ-induced nuclear localization of the Smads in ARPE-19 cells, but has little effect on p-smad2/3. In the presence of pirfenidone at concentration 0.5 mg/ml for 1h with TGFβ (10 ng/ml) for an additional 48 h, cell migration and expression of extracellular matrix induced by TGFβ, including collagen type I and fibronectin, can be inhibited in ARPE-19 cells[3]. Oral administration of pirfenidone, 300 mg/kg, daily for 4 weeks, can attenuates bleomycin-induced pulmonary fibrosis in mice[4]. Increased expression levels of TGF-β1, TNF-a and PDGF of idiopathic pulmonary fibrosis rat models can be converted to almost normal when the rats treated with 100 mg/kg pirfenidone once daily on day 15, 30 and 45[5]. Pirfenidone can attenuate the EMT process induced not only by exogenous TGF-β1 but also by paracrine TGF-β produced from NSCLC cells[6]. Up to now, pirfenidone treatment of idiopathic pulmonary fibrosis is approved by FDA (see https://www.fda.gov/).
作用机制
Pirfenidone can inhibit TGFβ expression or TGFβ-induced fibrogenesis by blocking nuclear translocation of Smads. But the mechanism for the process is unknown.
Pirfenidone/吡非尼酮 细胞实验
Cell Line
Concentration
Treated Time
Description
References
4T1 breast cancer cells
0.1 μg/mL
6, 24, and 48 h
To test the effect of Pirfenidone/m on mitochondrial activity of 4T1 breast cancer cells, showing no cytotoxicity
ACS Nano. 2023 Dec 26;17(24):24654-24667.
MLE-12 cells
100 μM
3 h
To evaluate the effect of Pirfenidone on MAVS expression, results showed that Pirfenidone failed to reduce MAVS expression.
Eur Respir J. 2021 Apr 15;57(4):2000652.
HFL-1 cells
1.5 mg/mL
48 h
To investigate the inhibitory effect of Pirfenidone on TGF β1-induced fibroblast differentiation. The results showed that Pirfenidone significantly inhibited TGF β1-induced a-SMA expression in a dose-dependent manner.
iScience. 2023 Apr 6;26(5):106586.
Human bronchial epithelial cells (HBE)
1 mM, 500 µM, 100 µM
24 h
To evaluate the effect of Pirfenidone on the expression of NOX4 and antioxidant genes in HBE cells from IPF patients. The results showed that Pirfenidone significantly reduced NOX4 expression and induced the expression of antioxidant genes in some patients.
2023 Feb 10;12(2):443. doi: 10.3390/antiox12020443.
Pancreatic acinar cells
0.5 mg/mL
30 min
To evaluate the effect of Pirfenidone on trypsin activation, results showed that Pirfenidone was unable to inhibit carbachol-induced trypsin activation.
JCI Insight. 2022 Jan 25;7(2):e141108.
Pancreatic acinar cells
0.5 mg/mL
4 h
To evaluate the effect of Pirfenidone on cytokine secretion, results showed that Pirfenidone pretreatment reduced the secretion of TNF-α and IL-6.
JCI Insight. 2022 Jan 25;7(2):e141108.
Macrophages
0.5 mg/mL
24 h
To evaluate the effect of Pirfenidone on macrophage polarization, results showed that Pirfenidone significantly reduced the secretion of M1 markers TNF-α and IL-6 and increased the expression of M2 markers IL-10, IL-4, and Arginase-1.
JCI Insight. 2022 Jan 25;7(2):e141108.
Th17 cells
10 µM
3 days
To evaluate the effect of Pirfenidone on Th17 differentiation, results showed that Pirfenidone significantly inhibited IL-17A secretion at 10 µM.
Cells. 2023 Dec 8;12(24):2795.
pancreatic acinar cells
0.5 mg/mL
30 min
To evaluate the effect of Pirfenidone on trypsin activation in pancreatic acinar cells, results showed that Pirfenidone was unable to inhibit carbachol-induced trypsin activation
JCI Insight. 2022 Jan 25;7(2):e141108.
pancreatic acinar cells
0.5 mg/mL
1 h
To evaluate the effect of Pirfenidone on trypsin activation in pancreatic acinar cells, results showed that Pirfenidone was unable to inhibit carbachol-induced trypsin activation
JCI Insight. 2022 Jan 25;7(2):e141108.
NCI-H460 cells
2.0 mM
48 h
To evaluate the effect of Pirfenidone combined with Paclitaxel on the growth of NCI-H460 cells, results showed that the combined treatment significantly reduced cell growth.
Int J Mol Sci. 2022 Mar 26;23(7):3631.
A549 cells
1.5 mM
48 h
To evaluate the effect of Pirfenidone combined with Paclitaxel on the growth of A549 cells, results showed that the combined treatment had a clear cytotoxic effect, but it was not statistically significant compared to individual treatments.
Int J Mol Sci. 2022 Mar 26;23(7):3631.
NCI-H322 cells
2 mM
48 h
To evaluate the effect of Pirfenidone combined with Paclitaxel on the growth of NCI-H322 cells, results showed that the combined treatment had a clear cytotoxic effect, but it was not statistically significant compared to individual treatments.
Int J Mol Sci. 2022 Mar 26;23(7):3631.
Pirfenidone/吡非尼酮 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Bleomycin-induced pulmonary fibrosis model
Oral administration
100 mg/kg
Once daily for 21 days
To evaluate the antifibrotic activity of Pirfenidone in a bleomycin-induced pulmonary fibrosis model, the results showed that Pirfenidone significantly alleviated pathological damage and collagen deposition in pulmonary fibrosis.
Acta Pharm Sin B. 2023 Feb;13(2):722-738.
Mice
4T1 and E0771 triple negative breast tumor models and MCA205 fibrosarcoma model
Intravenous injection
5 or 10 mg/kg
Once daily for 5 days
To test the effect of Pirfenidone/m on tumor microenvironment modulation, showing effective reduction in tumor stiffness, improved perfusion, and significant delay in primary tumor growth
ACS Nano. 2023 Dec 26;17(24):24654-24667.
Mice
Pulmonary fibrosis model
Intraperitoneal injection
40 mg/kg
Every 2 days until day 21
To evaluate the therapeutic effect of Pirfenidone on pulmonary fibrosis, results showed that the therapeutic effects of Pirfenidone were not related to MAVS signaling.
Eur Respir J. 2021 Apr 15;57(4):2000652.
C57BL/6 mice
Bleomycin-induced pulmonary fibrosis model
Intraperitoneal injection
100 mg/kg
Once daily for 14 days
To investigate the therapeutic effect of Pirfenidone on bleomycin-induced pulmonary fibrosis. The results showed that Pirfenidone significantly improved lung structure, reduced collagen deposition, and significantly downregulated the mRNA levels of FN.
iScience. 2023 Apr 6;26(5):106586.
Mice
Acute pancreatitis model
Oral gavage
400 mg/kg
Multiple doses, duration varies depending on the experimental model
To evaluate the therapeutic effect of Pirfenidone in acute pancreatitis models, results showed that Pirfenidone significantly reduced inflammation and injury in the pancreas and lungs.
JCI Insight. 2022 Jan 25;7(2):e141108.
Balb/c mice
Bleomycin-induced pulmonary fibrosis model
Oral
150 mg/kg
6 times per week for 2 weeks
To evaluate the therapeutic effect of Pirfenidone on bleomycin-induced pulmonary fibrosis, results showed that Pirfenidone improved lung function and reduced fibrotic changes.
Cells. 2023 Dec 8;12(24):2795.
Mice
Acute pancreatitis model
Oral gavage
400 mg/kg
Once daily for 2 days
To evaluate the effect of Pirfenidone in the treatment of acute pancreatitis models, results showed that Pirfenidone could alleviate inflammation and injury in the pancreas and lungs
JCI Insight. 2022 Jan 25;7(2):e141108.
Pirfenidone/吡非尼酮 动物研究
Dose
Mice[7] (p.o.): 200 mg/kg; rat[8] (p.o.): min = 50 mg/kg, max = 1000 mg/kg
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