Abstract:
INTRODUCTION:Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and organs. Increase in oxidative stress and platelet-derived growth factor receptor (PDGFR) activation promote collagen I (Col I) production, leading to fibrosis in SSc. Lipoic acid (LA) and its active metabolite dihydrolipoic acid (DHLA) are naturally occurring thiols that act as cofactors and antioxidants, and are produced by lipoic acid synthetase (LIAS). The goal of this study was to examine whether LA and LIAS was deficient in SSc patients and determine the effect of DHLA on the phenotype of SSc dermal fibroblasts. N-acetylcysteine (NAC), a commonly used thiol antioxidant, was included as a comparison. METHODS:Dermal fibroblasts were isolated from healthy subjects and patients with diffuse cutaneous SSc. Matrix metalloproteinase (MMPs), tissue inhibitors of MMPs (TIMP), plasminogen activator inhibitor-1 (PAI-1) and LIAS were measured by ELISA. The expression of Col I was measured by immunofluorescence, hydroxyproline assay, and quantitative PCR. PDGFR phosphorylation and α-smooth muscle actin (α-SMA) was measured by Western blotting. Student's t-tests were performed for statistical analysis and p-values of less than 0.05 with two-tailed analysis were considered statistically significant. RESULTS:The expression of LA and LIAS in SSc dermal fibroblasts was lower than normal fibroblasts, however LIAS was significantly higher in SSc plasma and appeared to be released from monocytes. DHLA lowered cellular oxidative stress, and decreased PDGFR phosphorylation, Col I, PAI-1, and α-SMA expression in SSc dermal fibroblasts. It also restored the activities of phosphatases that inactivated the PDGFR. SSc fibroblasts produced lower levels of MMP-1 and 3, and DHLA increased them. In contrast, TIMP-1 levels were higher in SSc but DHLA had minimal effect. Both DHLA and NAC increased MMP-1 activity when SSc cells were stimulated with PDGF. In general, DHLA showed better efficacy than NAC in most cases. CONCLUSIONS:DHLA not only acts as an antioxidant but also an antifibrotic since it has the ability to reverse the profibrotic phenotype of SSc dermal fibroblasts. Our study suggests that thiol antioxidants, including NAC and LA/DHLA, could be beneficial for patients with SSc.
journal_name
Arthritis Res Therjournal_title
Arthritis research & therapyauthors
Tsou PS,Balogh B,Pinney AJ,Zakhem G,Lozier A,Amin MA,Stinson WA,Schiopu E,Khanna D,Fox DA,Koch AEdoi
10.1186/s13075-014-0411-6subject
Has Abstractpub_date
2014-01-01 00:00:00pages
411issue
5eissn
1478-6354issn
1478-6362pii
s13075-014-0411-6journal_volume
16pub_type
杂志文章abstract:INTRODUCTION:Soluble immune aggregates bearing intact Fc fragments are effective treatment for a variety of autoimmune disorders in mice. The better to understand the mechanisms by which Fc-bearing immune complexes suppress autoimmunity, and to develop a platform for clinical translation, we created a series of fully r...
journal_title:Arthritis research & therapy
pub_type: 杂志文章
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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journal_title:Arthritis research & therapy
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更新日期:2013-01-01 00:00:00
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pub_type: 杂志文章
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pub_type: 杂志文章,多中心研究
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pub_type: 评论,社论
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