Role of 12/15-Lipoxygenase(LOX) in Patients with Systemic Sclerosis

Hirahito Endo, Makoto Kabraki, Koutarou Shikano, Sei Muraoka, Nahoko Tanaka, Tatsuhiro Yamamoto, Kanako Kitahara, Kaichi Kaneko, Yoshie Kusunoki, Natsuko Kusunoki, Kenji Takagi, Tomoko Hasunuma and Shinichi Kawai, Division of Rheumatology, Department of Internal Medicine, School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: fibroblasts and scleroderma

Session Information

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

Session Type: Abstract Submissions (ACR)

Background/Purpose: Recently 12/15-lipoxygenase (LOX) and it’s metabolites have a prominent anti-fibrotic role during dermal fibrosis in scleroderma experimental model using 12/15-LOX deficient mice were reported (Ann Rheum Dis. 2012,71,1081). To evaluate the role of 12/15-lipoxygenase (LOX) in patients with systemic sclerosis(SSc) we measured 12/15-LOX and these enzyme metabolites. Methods: SSc 32 patients:age57±10.3years old, disease duration 6.4±4.9years. dcSSc : lcSSc 20:12. control:RA 20 patients, normal healthy subjects 20. We measured the level of 12-LOX, 15-LOX mRNA in peripheral blood mononuclear cells(PBMC)of patients with SSc by real time quantitative PCR. 12-LOX and 15-LOX metabolites 12-(S)-Hydroxytetraenoic acid (HETE), 15-(S)-HETE and lipoin A₄(LXA₄)were measured by ELISA in plasma and bronchoalveolar lavage fluid (BALF) of patients with SSc. 15-LOX/12-LOX expression was measured by immunohistological analysis in biopsy specimens of dermal and interstitial pneumonia of patients with SSc.Results: Level of plasma 12-(S)-HETE of SSc was significantly higher than that of RA and normal subjects(SSc10.76±3.22, RA4.08±1.22,Control3.77±1.26ng/ml, P<0.01). Level of plasma lipoxin A₄of SSc was also higher than that of RA and control(SSc,3.39±1.79, RA 0.75±0.35, normal 0.77±0.30ng/ml). On the other hand level of plasma 15-(S)-HETE in SSc was lower than that of control (SSc2.07±1.18,RA3.76±1.82, normal2.39±0.98ng/ml). Plasma 12-(S)-HETE, LXA₄ levels in dcSSc patients were higher than that of lcSSc(dcSSc4.1±1.6,lcSSc1.86±0.85ng/ml). Expression of 12-LOXmRNA in PBMC of patients with SSc was higher than normal( SSc 4.7, control 1). Expression of 15LOX was not higher than SSc. BALF LXA₄and 15-LOX in lung biopsy specimens were lower than that of other interstitial pneumonia. Conclusion: Expression of platelet type 12-LOX was correlated with the progression of fibrotic lesion in patients with SSc. These data suggested that platelet type 12-LOX and 12-(S)-HETE may be increased for the negative feedback mechanisms for fibrosis because these enzymes and metabolites had anti-fibrotic effects. 12/15-LOX systems may contribute a new therapeutic approach in skin and organ involvement in patients with SSc.

Disclosure:

H. Endo,
None;

M. Kabraki,
None;

K. Shikano,
None;

S. Muraoka,
None;

N. Tanaka,
None;

T. Yamamoto,
None;

K. Kitahara,
None;

K. Kaneko,
None;

Y. Kusunoki,
None;

N. Kusunoki,
None;

K. Takagi,
None;

T. Hasunuma,
None;

S. Kawai,
None.

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