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Antifibrotic effect of Pirfenidone on orbital fibroblasts of patients with thyroid-associated ophthalmopathy by decreasing TIMP-1 and collagen levels.

Authors
Kim, H; Choi, YH; Park, SJ; Lee, SY; Kim, SJ; Jou, I; Kook, KH
Citation
Investigative ophthalmology & visual science, 51(6):3061-3066, 2010
Journal Title
Investigative ophthalmology & visual science
ISSN
0146-04041552-5783
Abstract
PURPOSE: The aim of this study was to determine the antifibrotic effects of pirfenidone in orbital fibroblasts of patients with thyroid-associated ophthalmopathy (TAO).



METHODS: The effects of interleukin (IL)-1beta and of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-beta on the induction of tissue inhibitors of metalloproteinases (TIMP)-1 were assessed in orbital fibroblasts of TAO patients. TIMP-1 protein levels were measured by ELISA and Western blot analyses, and TIMP-1 activity was assessed by reverse zymography. The effect of pirfenidone on TIMP-1 induction in orbital fibroblasts was evaluated with the same methods using dexamethasone as a reference agent. A hydroxyproline assay was used to determine the effect of pirfenidone and dexamethasone on collagen production in orbital fibroblasts, and the tetrazolium-based MTT assay was used to assess pirfenidone cytotoxicity.



RESULTS: IL-1beta strongly and dose dependently increased the level of active TIMP-1 protein, whereas FGF, PDGF, and TGF-beta did not significantly induce TIMP-1 protein. Pirfenidone was more effective than dexamethasone in inhibiting IL-1beta-induced increases in TIMP-1, reducing TIMP-1 levels to less than those in untreated controls at a minimal concentration (5 mM). Moreover, pirfenidone effectively decreased hydroxyproline levels in orbital fibroblasts, whereas dexamethasone had no effect on hydroxyproline levels. Pirfenidone exhibited no toxicity in orbital fibroblasts at the concentrations used.



CONCLUSIONS: These results indicate that nontoxic concentrations of pirfenidone have significant antifibrotic effects on orbital fibroblasts from patients with TAO.
MeSH terms
AdultAgedAnti-Inflammatory Agents, Non-Steroidal/*pharmacologyBlotting, WesternCell Culture TechniquesCell SurvivalCollagen/*metabolismDexamethasone/pharmacologyDose-Response Relationship, DrugEnzyme-Linked Immunosorbent AssayFemaleFibroblasts/*drug effects/metabolismGraves Ophthalmopathy/metabolism/pathology/*prevention & controlHumansHydroxyproline/metabolismIntercellular Signaling Peptides and Proteins/pharmacologyInterleukin-1beta/pharmacologyMaleMiddle AgedOrbit/*drug effects/metabolismPyridones/*pharmacologyTissue Inhibitor of Metalloproteinase-1/*metabolismTumor Necrosis Factor-alpha/antagonists & inhibitorsYoung Adult
DOI
10.1167/iovs.09-4257
PMID
20053983
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Journal Papers > School of Medicine / Graduate School of Medicine > Ophthalmology
AJOU Authors
주, 일로국, 경훈
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