Role of apoptosis and transforming growth factor β1 in fibroblast selection and activation in systemic sclerosis

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Abstract
Objective We hypothesized that pathophysiologic events during the development of systemic sclerosis (SSc) may lead to selection and propagation of certain apoptosis-resistant fibroblast subpopulations. The aim of this study was to examine a possible role for apoptosis in fibroblast selection in SSc and the role of transforming growth factor β1 (TGFβ1). Methods We compared SSc and normal fibroblasts for their susceptibility to anti-Fas–induced apoptosis and analyzed 2 models that might lead to fibroblast resistance to apoptosis in this process: long-term exposure to either anti-Fas or TGFβ1. Results SSc-derived fibroblasts were resistant to anti-Fas–induced apoptosis, showing 5.5 ± 17.2% (mean ± SD) apoptosis, compared with 32.1 ± 14.0% among normal fibroblasts (P < 0.05). Anti-Fas–selected normal fibroblasts showed 9.0 ± 3.7% apoptosis, compared with 21.6 ± 5.9% for sham-treated cells, which is consistent with the elimination of apoptosis-susceptible subpopulations. Normal fibroblasts subjected to 6 weeks of TGFβ1 treatment showed not only resistance to apoptosis, but also proliferation (118.5 ± 35.4%), after anti-Fas treatment, compared with sham-treated cells (35.1 ± 11.1% apoptotic cell death). TGFβ1 treatment also increased the proportion of myofibroblasts (47% versus 28% in controls). Cultured SSc fibroblasts had a greater proportion of myofibroblasts (32–83%) than did normal fibroblasts (4–25%). We also examined the relationship between collagen gene expression and the myofibroblast phenotype in normal and SSc skin sections. Only 2 of 7 normal sections had α-smooth muscle actin (α-SMA)–positive cells (mean ± SD score 0.29 ± 0.49 on a scale of 0–3), but all SSc sections were positive for α-SMA, with a mean score of 1.90 ± 0.88 for lesional and 1.50 ± 0.71 for nonlesional sections. Scores for α1(I) procollagen messenger RNA (mRNA) in lesional skin (mean ± SD 3.30 ± 0.82 on a scale of 1–4) were significantly higher than in normal (1.43 ± 0.79) or nonlesional (1.40 ± 0.52) skin, but scores varied, and there was no correlation between collagen mRNA and α-SMA levels. Conclusion Our results show that resistance to apoptosis is an important part of the SSc phenotype. TGFβ1 may play a role by inducing apoptosis-resistant fibroblast populations, and also by inducing myofibroblasts and by enhancing extracellular matrix synthesis.

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