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Increased circulating levels of tissue kallikrein in systemic sclerosis correlate with microvascular involvement
  1. A Del Rosso1,
  2. O Distler2,
  3. A F Milia1,
  4. C Emanueli3,
  5. L Ibba-Manneschi5,
  6. S Guiducci1,
  7. M L Conforti1,
  8. S Generini1,
  9. A Pignone1,
  10. S Gay2,
  11. P Madeddu4,
  12. M Matucci-Cerinic1
  1. 1Department of Medicine, Division of Rheumatology, University of Florence, Florence, Italy
  2. 2Centre of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
  3. 3Molecular and Cellular Medicine, INBB, Alghero, Italy
  4. 4Experimental Medicine and Gene Therapy, INBB, Osilo and Alghero, Italy; and Internal Medicine, University of Sassari, Sassari, Italy
  5. 5Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
  1. Correspondence to:
    Professor M Matucci Cerinic
    Department of Medicine, Division of Rheumatology, University of Florence, Viale G Pieraccini, 18–50139 Florence, Italy;


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.

  • 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
  • kallistatin
  • nailfold capillaroscopy
  • systemic sclerosis
  • tissue kallikrein

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