Effects of Pirfenidone on Proliferation, Migration, and Collagen Contraction of Human Tenon’s Fibroblasts In Vitro

Lin, Xianchai; Yu, Minbin; Wu, Kaili; Yuan, Hongzhi; Zhong, Hua

doi:10.1167/iovs.08-2815

Cited by 100 publications

(92 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In agreement with in vivo model data, in vitro antiproliferative effects of PFD were also confirmed with human leiomyoma cells [10], human Tenon fibroblasts [11], and rat cardiac fibroblasts [12]. Notably, Lin et al [11] have reported that PFD suppressed cell proliferation of human Tenon fibroblasts by inducing G0/G1 cell cycle arrest. Other reports have demonstrated antiproliferative effects of PFD in cancer-associated fibroblasts derived from human lung cancer patients [13] and myofibroblast-like pancreatic stellate cells (PSCs) derived from human pancreatic cancer patients [14].…”

Section: Introductionsupporting

confidence: 76%

“…Specifically, PFD was shown to be effective in various in vivo models including a rat model of myocardial infarction [5,6], a mouse model of pulmonary fibrosis [7], a mouse model of nonalcoholic steatohepatitis [8], and a rats model of renal fibrosis [9]. In agreement with in vivo model data, in vitro antiproliferative effects of PFD were also confirmed with human leiomyoma cells [10], human Tenon fibroblasts [11], and rat cardiac fibroblasts [12]. Notably, Lin et al [11] have reported that PFD suppressed cell proliferation of human Tenon fibroblasts by inducing G0/G1 cell cycle arrest.…”

Section: Introductionmentioning

confidence: 56%

See 1 more Smart Citation

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

et al. 2019

View full text Add to dashboard Cite

Background: Pirfenidone (PFD), which is an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis, induces G0/G1 cell cycle arrest in fibroblasts. We hypothesized that PFD-induced G0/G1 cell cycle arrest might be achieved in other types of cells, including cancer cells. Here we investigated the effects of PFD on the proliferation of pancreatic cancer cells (PCCs) in vitro. Method: Human skin fibroblasts ASF-4-1 cells and human prostate stromal cells (PrSC) were used as fibroblasts. PANC-1, MIA PaCa-2, and BxPC-3 cells were used as human PCCs. Cell cycle and apoptosis were analyzed using flow cytometer. Results: First, we confirmed that PFD suppressed cell proliferation of ASF-4-1 cells and PrSC and induced G0/G1 cell cycle arrest. Under these experimental conditions, PFD also suppressed cell proliferation and induced G0/G1 cell cycle arrest in all PCCs. In PFD-treated PCCs, expression of p21 was increased but that of CDK2 was not clearly decreased. Of note, PFD did not induce significant apoptosis among PCCs. Conclusions: These results demonstrated that the antifibrotic agent PFD might have antiproliferative effects on PCCs by inducing G0/G1 cell cycle arrest. This suggests that PFD may target not only fibroblasts but also PCCs in the tumor microenvironment of pancreatic cancer.

show abstract

Section: Introductionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 56%

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

et al. 2019

View full text Add to dashboard Cite

show abstract

“…26 Controlling the balance of fibroblasts and myofibroblasts is thought to be critical in postoperative healing. Clinical studies observed increased levels of TGF-b in both conjunctival tissue and aqueous humor of postfiltration surgery patients, 26,27 which might stimulate the proliferation and migration capacity of HTFs in vivo, resulting surgical failure. Transforming growth factor-b2 is recognized as the predominant isoform of all three isoforms in humans and is implicated in the pathogenesis of several ocular fibrosis diseases.…”

Section: Discussionmentioning

confidence: 99%

Tetramethylpyrazine Attenuates Transdifferentiation of TGF-β2–Treated Human Tenon's Fibroblasts

Cai

Yang

Chen

et al. 2016

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

Citation: Cai X, Yang Y, Chen P, et al. Tetramethylpyrazine attenuates transdifferentiation of TGF-b2-treated human Tenon's fibroblasts. Invest Ophthalmol Vis Sci. 2016;57:4740-4748. DOI:10.1167/iovs.16-19529 PURPOSE. To investigate the pharmacologic effect of tetramethylpyrazine (TMP) on human Tenon's fibroblasts (HTFs), the cells implicated in scarring after filtration surgery. METHODS.Transforming growth factor-b2 (TGF-b2) was used to stimulate a fibrotic phenotype in primary HTFs, and the influence of TMP on the fibrotic phenotype was assessed. Cell proliferation and cell cycle regulation were profiled. Immunofluorescence staining tracked proliferating cell nuclear antigen (PCNA) expression. Transwell assays monitored cell migration. Flow cytometry measured TMP toxicity. In addition, in TGF-b2-treated HTFs, Western blot and immunofluorescence were employed to assess the expression of a-smooth muscle actin (a-SMA). The TMP-mediated activity on cytoskeletal arrangements and extracellular matrix (ECM) accumulation in HTFs was evaluated using actin polymerization and Western blot assays. Moreover, TGF-b-dependent activation of Smad3 and p38 was examined by Western blot analysis. RESULTS.In TGF-b2-treated HTFs, TMP reduced proliferation and migration but did not induce apoptosis. Moreover, TMP attenuated expression of a-SMA and suppressed stress fiber formation stimulated by profibrotic cytokine; it also counteracted TGF-b2-induced cytoskeletal rearrangements, morphologic changes, and ECM accumulation. Smad3 and p38 mitogenactivated protein kinase (MAPK) signaling were downstream of the TMP-sensitive effect.CONCLUSIONS. Tetramethylpyrazine counteracts TGF-b2-mediated myofibroblast transdifferentiation and attenuates ECM component deposition and cell proliferation in HTFs, implicating TMP as a potential antifibrosis agent in glaucoma filtration surgery.

show abstract

“…The in vitro antifibrotic activities of pirfenidone (table 3) fall into three general categories: reduction of fibroblast and myofibroblast proliferation [79,[84][85][86], inhibition of extracellular matrix synthesis/deposition [79][80][81][82][83]86], and reductions in fibrotic markers [81,82,84,85]. Each of these activities is relevant to the attenuation of chronic fibrosis, is consistent with the effects reported for pirfenidone in animal models, and may be relevant to the use of pirfenidone in the treatment of IPF.…”

Section: Effects In Cell-based Assaysmentioning

confidence: 99%

Antifibrotic activities of pirfenidone in animal models

Schaefer¹,

Ruhrmund²,

Lin³

et al. 2011

European Respiratory Review

385

287

View full text Add to dashboard Cite

Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-b. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component. KEYWORDS: Animal model, antifibrotic, fibrosis, idiopathic pulmonary fibrosis, pirfenidone F ibrosis, the dysregulated deposition of extracellular matrix (ECM) with progressive destruction of normal tissue, is a primary or contributing factor in chronic disease states in several organs. Pulmonary fibrosis is associated with numerous diffuse parenchymal lung diseases, of which the most common are idiopathic pulmonary fibrosis (IPF) and sarcoidosis [1]. Cardiac fibrosis is associated with chronic heart failure, atrial fibrillation, and cardiac remodelling following acute myocardial infarction [2,3]. Renal fibrosis is associated with multiple forms of chronic kidney disease and correlates with impairment of kidney function [4,5]. Hepatic fibrosis is associated with chronic hepatitis B and C viral infections and nonalcoholic steatohepatitis [6]. Each of these conditions represents a significant unmet medical need, warranting significant research and clinical study into treatment for fibrotic disease.Pirfenidone (Esbriet1, Pirespa1) is an orally active small molecule comprising a modified phenyl pyridone ( fig. 1). The compound exhibits well documented antifibrotic and anti-inflammatory activities in a variety of animal and cellbased models, although its molecular target has not been elucidated. Pirfenidone was initially identified as having anti-inflammatory activity in animal models and evaluated for use as an antiinflammatory drug [7,8]. However, the unexpected identification of antifibrotic effects in animals treated with pirfenidone redefined the interest in the compound [9]. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models, including fibrosis of the lung, liver, heart and kidney.The most extensive clinical studies of pirfenidone are for treatment of IPF, a chronic interstitial lung disease characterised by the unregulated deposition of ECM leading to the unremitting destruction of normal lung. Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure. The estimated median survival upon diagnosis is approximately ...

show abstract

Effects of Pirfenidone on Proliferation, Migration, and Collagen Contraction of Human Tenon’s Fibroblasts In Vitro

Abstract: These findings indicate that pirfenidone inhibits proliferation, migration, and collagen contraction of HTFs at nontoxic concentrations. A decrease in autocrine TGF-beta signaling may have a role in the effects of pirfenidone.

Cited by 100 publications

References 24 publications

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

Tetramethylpyrazine Attenuates Transdifferentiation of TGF-β2–Treated Human Tenon's Fibroblasts

Antifibrotic activities of pirfenidone in animal models

Contact Info

Product

Resources

About