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).

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.

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.

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.