Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's I
Session Type: Abstract Submissions (ACR)
Systemic sclerosis (SSc) is a connective tissue disease characterized by vasculopathy and 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. The goal of this study was to examine whether LA, and lipoic acid synthetase (LIAS), the enzyme producing LA, were deficient in SSc patients. The effect of DHLA on the phenotype of SSc dermal fibroblasts was also determined. N-acetylcysteine (NAC), a commonly used thiol antioxidant, was included as a comparison.
Dermal fibroblasts were isolated from punch biopsies from healthy subjects and patients with diffuse cutaneous SSc. Oxidative stress was measured by dihydroethidium staining and hydrogen peroxide fluorescent assay. Immunofluorescence was performed to probe for LA, Col I and α-smooth muscle actin (αSMA). Matrix mettaloproteinase-1 (MMP-1) and 3, LIAS were measured by ELISA. Expression of phosphatases, PDGFR phosphorylation, and αSMA was measured by Western blotting.
The expression of LA and LIAS in SSc dermal fibroblasts was lower than normal, however LIAS was significantly higher in SSc plasma (normal 79.5±6.0 vs. SSc 119.5±14.2 pg/ml, p<0.05). DHLA lowered cellular hydrogen peroxide (basal 2487±252 vs. plus DHLA 1908±61 fluorescent unit, p<0.05), and decreased PDGFR phosphorylation, Col I, and αSMA 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 then did normal fibroblasts (MMP-1: normal 15161±3525 vs. SSc 2094±405 pg/ml; MMP-3: normal 714±189 vs. SSc 216±69 pg/ml, both p<0.05), with levels increasing after DHLA incubation (MMP-1: 4789±1406 and MMP-3: 407±143 pg/ml, p<0.05 vs. without DHLA). DHLA showed better efficacy than NAC in most cases.
Conclusion: DHLA decreased PDGFR activation and increased MMPs that degrade Col I. It also lowered αSMA expression in SSc dermal fibroblasts. Since LA and LIAS were deficient in SSc dermal fibroblasts, this might be one of the reasons DHLA was beneficial. DHLA not only acted as an antioxidant but also an antifibrotic since it had the ability to reverse the profibrotic phenotype of SSc dermal fibroblasts.
P. S. Tsou,
A. J. Pinney,
D. A. Fox,
A. E. Koch,
Eli Lilly and Company: I am currently employed by Eli Lilly with an adjunct appointment at University of Michigan. My work at Lilly is not relevant to the content of the abstract.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lipoic-acid-plays-a-crucial-role-in-scleroderma-dermal-fibroblasts/