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S100A8/A9 in bleomycin-induced skin fibrosis
  1. K Andréasson1,
  2. R Gustafsson2,
  3. F Ivars2,
  4. J Roth3,
  5. T Vogl3,
  6. R Hesselstrand1,
  7. D Heinegärd1,
  8. T Saxne1
  1. 1Department of Clinical Sciences, Lund University, Lund, Sweden
  2. 2Departement of Experimental Medical Science, Lund University, Lund, Sweden
  3. 3Institute of Immunology, University of Münster, Münster, Germany

Abstract

Background and objectives Systemic sclerosis is a heterogeneous disease characterised both by inflammation and fibrosis. TLR4-dependent signalling has been proposed to play a significant role in the connection between inflammation and fibrosis in SSc. We have previously found increased levels of the TLR4-agonist S100A8/A9 in both serum and faeces of patients with SSc. In this study, we examined the role of S100A8/A9 in the pathogenesis of inflammation induced skin fibrosis in the bleomycin mouse model.

Materials and methods S100A9-/- mice were kept on a C57 Bl/6 background. These mice lack biologically active S100A8/A9 protein complex. Wild type (WT) littermates were used as controls. In total, 40 age matched female mice were used. Skin fibrosis was induced by 12 subcutaneous injections of bleomycin over a 4 week period. Dermal skin thickness was evaluated by light microscopy and skin collagen content by measurement of hydroxyproline. Skin concentration of water and fat was evaluated after freeze-drying and fat extraction of skin biopsies with acetone respectively. Punch biopsies were taken for later mRNA quantification by rtPCR and for electron microscopy.

Results Skin thickness increased to a similar extent in WT and S100A9-/- mice compared to saline injected animals after bleomycin treatment (262 ± 11 μm vs 263 ± 12 μm). The amount of collagen also increased to the same level in WT and S100A9-/- mice (53 ± 1.6 vs 53 ± 0.9 μg/mm2). Compared to saline injected control mice, bleomycin treatment resulted in an increase in skin water content in WT (70 ± 0.6 vs 65 ± 1.3 %; p < 0.001) but not in the S100A9-/- mice (68 ± 1.3 vs 68 ± 0.5 %). Bleomycin treatment caused a more pronounced reduction of dry skin fat content in WT (41 ± 2.6 in saline vs 17 ± 1.6 % in bleomycin treated mice; p < 0.001) than in S100A9-/- mice (36 ± 1.4 vs 23 ± 2.2 %; p = 0.002).

Conclusion S100A9 deficiency does not protect mice from bleomycin induced skin fibrosis. S100A9 deficiency seems to attenuate inflammatory changes of skin composition in the bleomycin mouse model of skin fibrosis.

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