Evidence of 5-lipoxygenase overexpression in the skin of patients with systemic sclerosis - A newly identified pathway to skin inflammation in systemic sclerosis

Objective. Leukotrienes are a family of arachidonic acid derivatives with p otent proinflammatory and profibrotic properties, and 5-lipoxygenase (5-LOX ) catalyzes two key steps in the leukotriene biosynthetic pathway. Since in flammatory cell infiltrates and excessive fibrosis are hallmarks of systemi c sclerosis (SSc) skin lesions, we undertook the present study to investiga te the expression of 5-LOX in skin biopsy specimens from patients with SSc. Methods. Expression of 5-LOX in skin sections from 10 SSc patients and 8 he althy controls was examined by in situ hybridization with specific riboprob es and by immunohistochemistry analysis with 5-LOX monoclonal antibodies. S ynthesis of 5-LOX by cultured dermal fibroblasts from 7 patients with SSc a nd 4 controls was measured by fluorescence-activated cell sorter analysis. In addition, concentrations of leukotriene B-4 (LTE4) and LTE4 in fibroblas t supernatants after stimulation were determined using enzyme immunoassays. Results. Expression of 5-LOX was found in all skin sections from SSc patien ts as well as from controls. However, the number and percentage of 5-LOX-po sitive cells were significantly higher in SSc skin sections compared with c ontrol sections. Expression of 5-LOX was seen in cells within perivascular inflammatory infiltrates as well as in fibroblasts throughout the skin. The experiments with cultured skin fibroblasts revealed that 5-LOX was constit utively expressed in these cells, which resulted in the production of leuko trienes after cell stimulation. Whereas no difference was found for LTE4, S Sc fibroblasts produced significantly higher amounts of LTB4 after stimulat ion, compared with healthy control fibroblasts. Conclusion. The results of this study suggest that the 5-LOX pathway may be of significance in the pathogenesis of SSc and may represent a target for new treatment strategies.