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Abstract Number: 1503

Effect of Thiol Antioxidants On the Profibrotic Phenotype of Scleroderma Dermal Fibroblasts

Pei-Suen Tsou1, Beatrix Balogh2, Adam J. Pinney2, Elena Schiopu3, Dinesh Khanna4 and Alisa E. Koch5, 1Internal Medicine, Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 2University of Michigan Medical School, Ann Arbor, MI, 3Rheumatology/Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, 4Division of Rheumatology, University of Michigan Medical Center, Ann Arbor, MI, 5Internal Medicine - Rheumatology, University of Michigan Medical School, Ann Arbor, MI

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: fibroblasts and scleroderma

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Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Systemic sclerosis (Scleroderma, SSc) is a connective tissue disease characterized by vasculopathy and fibrosis of the skin and organs. Increase in superoxide production and platelet-derived growth factor receptor (PDGFR) activation promote collagen I (Col I) production, leading to fibrosis in SSc. Protein tyrosine phosphatases (PTPs), which are responsible for terminating the PDGFR pathway, are oxidatively inactivated in SSc dermal fibroblasts. In addition, these cells exhibit myofibroblast characteristics with increased α-smooth muscle actin (αSMA) expression. The goal of this study is to determine the effect of two thiol antioxidants, N-acetylcysteine (NAC) and dihydrolipoic acid (DHLA), on the phenotype of SSc fibroblasts, namely PDGFR stimulation, Col I synthesis, superoxide levels, phosphatase activities, αSMA expression, and matrix metalloproteinase 1 (MMP-1) production. 

Methods:

Punch biopsies (4 mm) from distal skin were obtained from patients with SSc (n=5). Normal (NL) skin tissue was obtained from the tissue procurement service of the University of Michigan. Superoxide levels were measured using dihydroethidium. PDGFR phosphorylation was determined by immunoprecipitation and Western blotting. Quantitative PCR was performed with primers for Col I and β-actin. Immunofluorescence was performed to probe for Col I and αSMA. An enzyme linked immunosorbent assay was completed to detect MMP-1. Phosphatase activities were measured using the amount of phosphate released as an end point. 

Results:

Addition of NAC decreased superoxide in SSc dermal fibroblasts while DHLA did not. Both NAC and DHLA decreased PDGFR phosphorylation in SSc fibroblasts. Col I mRNA was increased in SSc fibroblasts compared to normal (NL) at basal level, while NAC and DHLA decreased both Col I mRNA and protein levels. SSc fibroblasts produced lower levels of MMP-1 compared to NL, but the levels increased after NAC or DHLA incubation. DHLA not only decreased the expression of αSMA in SSc dermal fibroblasts, but also restored the activities of phosphatases that inactivate the PDGFR, including PTP1B, SHP-2, and DEP-1. Almost as effective was NAC which restored PTP1B and DEP-1 activity, but not SHP-2.

Conclusion:

Our results show that thiol antioxidants are beneficial for SSc dermal fibroblasts due to their ability to reverse the profibrotic phenotype of these cells. Thiol antioxidants decrease PDGFR activation, possibly by restoring the activities of phosphatases, and hence decrease Col I production. In addition, they increase MMP-1 production, which degrades Col I. Moreover, DHLA lowered the expression of αSMA, suggesting that it could reverse the myofibroblast phenotype of SSc dermal fibroblasts. Hence thiol antioxidants could prove to be an effective treatment in SSc.


Disclosure:

P. S. Tsou,
None;

B. Balogh,
None;

A. J. Pinney,
None;

E. Schiopu,

United Therapuetics,

8;

D. Khanna,

Actelion, Gilead, Genentech, ISDIN, and United Therapeutics,

2,

Actelion, Gilead, Genentech, ISDIN, and United Therapeutics,

5,

Actelion, Gilead, Genentech, ISDIN, and United Therapeutics,

8;

A. E. Koch,
None.

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