Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: Eicosanoids are a group of arachidonic acid-derived lipid mediators which play a key role in the regulation of inflammatory response and connective tissue remodeling. Different classes of eicosanoids exert different, often opposing roles. Leukotrienes (LTs), synthesized through the action of 5-lipoxygenase, are considered pro-inflammatory and pro-fibrotic mediators, while 15-lipoxygenase-derived products, 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxins, possess anti-inflammatory and anti-fibrotic properties, in part due to antagonizing action of LTs.
We undertook this study to investigate the role of eicosanoids in the pathogenesis of SSc trough evaluation of 1). the profile of eicosanoids synthesized by peripheral blood mononuclear cells (PBMC) and 2). relationships between eicosanoid profile of PBMC and clinical features and progression of the disease in patients with SSc.
Methods: Leukotriene B4 (LTB4), cysteinyl leukotrienes (CysLTs), and 15-HETE were measured by ELISA in the supernatants from ionophore-stimulated PBMC of 39 patients with SSc and 24 age- and sex-matched healthy controls (HC). Only patients, who had not received immunosuppressive drugs, aspirin or other NSAIDs before the study, were included. Follow-up data were available in 25 SSc patients (mean +/- SD follow-up time: 34 +/- 18 months). Disease progression was defined as death due to SSc-related organ complication, development of a new or progression of pre-existing SSc-related organ involvement.
Results: Concentration of LTB4 was significantly higher in PBMC cultures from patients with SSc (640 +/- 518 pg/mL/105cells) as compared with HC (353 +/- 216 pg/mL/105cells, p<0.05). Higher LTB4 levels were associated with the presence of diffuse SSc and pulmonary fibrosis. No significant differences could be found in the concentrations of CysLTs or 15-HETE between SSc patients and HC (data not shown). The 15-HETE/LTB4 and 15-HETE/CysLTs ratios were lower in SSc patients (13 +/- 11 and 20 +/- 19, respectively) as compared with HC (26 +/- 28, p<0.05, and 26 +/- 17, p=0.08, respectively),
In 7 SSc patients who experienced subsequent progression of the disease baseline concentration of CysLTs was significantly higher (452+/- 197 pg/mL/105cells) while 15-HETE/LTB4 (6.9 +/- 9.3) and 15-HETE/CysLTs (8.1 +/- 6.0) ratios – significantly lower as compared with the remaining 18 with stable disease (276+/- 139 pg/mL/105cells, 13.2+/- 10.7, and 18.9+/- 11.6, respectively, p<0.05 for all). Although LTB4 concentration was higher in patients who progressed over time (918+/- 665 pg/mL/105cells) as compared with those with stable disease (569+/- 549 pg/mL/105cells), the difference was not significant (p=0.1).
Conclusion: The results of our study indicate that increased synthesis of LTs, which is not balanced by sufficient synthesis of 15-lipoxygenase derived eicosanoids, might be involved in the pathogenesis and progression of SSc. Consequently, inhibition of LTs synthesis or action might represent a new, promising target in the treatment of SSc.
Disclosure:
O. M. Kowal-Bielecka,
None;
A. Lapinska,
None;
M. Bielecki,
None;
O. Distler,
Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,
2,
Actelion, Pfizer, Boehringer-Ingelheim, Bayer, Roche, Ergonex, BMS, Sanofi-Aventis, United BioSource Corporation, medac, Biovitrium, Novartis and Active Biotec,
5,
Actelion, Pfizer and Ergonex,
8;
I. Domyslawska,
None;
L. Chyczewski,
None;
S. Sierakowski,
None;
S. Gay,
None;
K. Kowal,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-synthesis-of-leukotrienes-by-peripheral-blood-mononuclear-cells-is-associated-with-more-severe-disease-and-worse-prognosis-in-patients-with-systemic-sclerosis/