These data provide evidence that GBCA exposure in ex vivo skin from healthy individuals increases fibroblast proliferation and has effects on the enzyme/inhibitor system that regulates collagen turnover in the skin.

Healing of superficial skin wounds depends on the proliferation and migration of keratinocytes at the wound margin. When human epidermal keratinocytes were incubated on polymerized type I collagen, they rapidly attached and spread. The cells underwent a proliferative response and, over the subsequent 6-day period, covered the collagen surface with a monolayer of cells. When keratinocytes were plated on collagen that had been fragmented by exposure to matrix metalloproteinase-1 (MMP-1, collagenase-1), the cells attached as readily as to intact collagen but spread more slowly and less completely. Growth was reduced by approximately 50%. Instead of covering the collagen surface, the keratinocytes remained localized to the site of attachment. Keratinocytes on fragmented collagen expressed a more differentiated phenotype as indicated by a higher level of surface E-cadherin. Based on these findings, we suggest that damage to the underlying collagenous matrix may impede efficient keratinocyte function and retard wound closure.

Objective Nephrogenic systemic fibrosis (NSF) is a clinical syndrome occurring in a small subset of patients with end stage renal disease (ESRD). Exposure to certain of the gadolinium-based contrast agents (GBCAs) during magnetic resonance imaging appears to be a trigger. The pathogenesis of the disease is largely unknown. The present study addresses potential patho-physiological mechanisms. Materials and Methods Here we have compared responses in organ-cultured skin and skin fibroblasts from individuals with ESRD to responses of healthy control subjects to Omniscan treatment. Results Treatment of skin from ESRD patients with Omniscan stimulated production of matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinases-1 (TIMP-1), but not type I procollagen. The same treatment also stimulated an increase in hyaluronan production. Similar results were seen with skin from normal controls but basal levels were higher in ESRD patients. Fibroblasts in monolayer culture gave the same responses but there were no differences based on whether the cells were isolated from the skin of healthy subjects or those with ESRD. Conclusion These data indicate that Omniscan exposure alters an enzyme / inhibitor system responsible for regulating collagen turnover in the skin and directly stimulates hyaluronan production. The higher basal levels of type I procollagen, MMP-1, TIMP-1 and hyaluronan in the skin from ESRD patients could contribute to the sensitivity of this patient population to fibrotic changes which might be induced by exposure to some of the GBCAs.