EXTENDED REPORT

Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement

A Del Rosso¹, O Distler², A F Milia¹, C Emanueli³, L Ibba-Manneschi⁵, S Guiducci¹, M L Conforti¹, S Generini¹, A Pignone¹, S Gay², P Madeddu⁴, M Matucci-Cerinic¹

¹ Department of Medicine, Division of Rheumatology, University of Florence, Florence, Italy
² Centre of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
³ Molecular and Cellular Medicine, INBB, Alghero, Italy
⁴ Experimental Medicine and Gene Therapy, INBB, Osilo and Alghero, Italy; and Internal Medicine, University of Sassari, Sassari, Italy
⁵ Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy

Correspondence to:
Correspondence to:
Professor M Matucci Cerinic
Department of Medicine, Division of Rheumatology, University of Florence, Viale G Pieraccini, 18–50139 Florence, Italy; cerinic{at}unifi.it

Background: In systemic sclerosis (SSc) the lack of an angiogenic response to hypoxia may be due to inappropriate synthesis of angiogenic and angiostatic factors. Tissue kallikrein (t-kallikrein), regulating the kallikrein-kinin system and acting on the microcirculation, is a potent angiogenic agent, and kallistatin is its natural inhibitor.

Objective: To evaluate, in patients with SSc, t-kallikrein and kallistatin levels and their correlation with clinical features and measures of microvascular involvement.

Patients and methods: Serum levels of t-kallikrein and kallistatin (ELISA) and t-kallikrein skin expression (immunohistochemistry) were studied in patients with SSc, and evaluated for subset (dSSc or lSSc), clinical and immunological features, and microvascular involvement (ulcers, telangiectasias, nailfold videocapillaroscopy).

Results: Circulating levels of t-kallikrein were higher in SSc than in controls (p<0.001). T-kallikrein did not differ between lSSc and dSSc, although it was higher in lSSc than in controls (p<0.001).T-kallikrein levels were higher in patients with early and active capillaroscopic pattern than in those with late pattern (p = 0.019 and 0.023). Patients with giant capillaries and capillary microhaemorrhages had higher t-kallikrein concentrations than patients with architectural derangement (p = 0.04). No differences in kallistatin levels were detected between patients with SSc and controls, or between lSSc and dSSc. In early SSc skin, the presence of t-kallikrein was found in endothelial and in perivascular inflammatory cells, while no staining in skin of advanced SSc was detected.

Conclusion: T-kallikrein levels are increased in patients with SSc, particularly in lSSc, and are associated with early and active capillaroscopic patterns. T-kallikrein may play a part in SSc microvascular changes.

Abbreviations: ACA, anticentromere antibodies; dSSc, diffuse cutaneous systemic sclerosis; ELISA, enzyme linked immunosorbent assay; KKS, kallikrein-kinin system; lSSc, limited cutaneous systemic sclerosis; SSc, systemic sclerosis; VEGF, vascular endothelial growth factor

Keywords: kallistatin; nailfold capillaroscopy; systemic sclerosis; tissue kallikrein

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