Nephrogenic systemic fibrosis (NSF) is a fibrotic disease generating intense interest due to its recent discovery, and unknown cause. It appears confined to patients with renal disease and presents as grossly thickened, indurated, tight skin that is woody to palpation. Histologically, the dermis contains thickened
collagen bundles, numerous plump fibroblast-like cells, and elevated
hyaluronan expression. Recent data suggest a link between the use of
gadolinium chelate as an MRI
contrast agent and the onset of the disease. Fibroblasts from the lesions of six NSF patients, all of whom were exposed to
gadodiamide, were compared with control fibroblasts for
hyaluronan and
collagen synthesis. Serum from NSF patients was assessed for fibroblast
hyaluronan-stimulating activity,
collagen synthesis, and
gadodiamide for its effect on fibroblast proliferation and matrix synthesis. NSF fibroblasts synthesized excess levels of
hyaluronan and
collagen compared with control fibroblasts, with up to 2.8-fold and 3.3-fold increases, respectively. NSF patient serum stimulated control fibroblast
hyaluronan synthesis by up to 7-fold, and
collagen synthesis by up to 2.4-fold. 1 mM
gadodiamide added to culture medium stimulated fibroblast growth in a dose-dependent manner, decreasing their doubling time from 28 h to 22 h, and increasing the maximum cell density. Even a short exposure to
gadodiamide stimulated cell growth, suggesting that the cells were activated by the
gadodiamide. The growth of fibroblasts within contracted
collagen lattices was also significantly stimulated by
gadodiamide, while fibroblasts exposed to
gadodiamide synthesized increased levels of
hyaluronan. Control fibroblasts exposed to
gadodiamide, and NSF fibroblasts exhibited an extensive pericellular coat of
hyaluronan, and expressed alpha-smooth muscle actin.
Gadolinium chloride did not affect fibroblast growth. This report demonstrates that NSF fibroblasts synthesize excess levels of
hyaluronan and
collagen, and that
gadodiamide stimulates control fibroblast growth, matrix synthesis, and differentiation into myofibroblasts, suggesting a possible role for
gadodiamide in the pathophysiology of NSF.