Induction of the expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents

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Abstract
Objective Nephrogenic systemic fibrosis (NSF) is a severe fibrosing disorder occurring in patients with renal insufficiency. The majority of patients with this disorder have documented exposure to magnetic resonance imaging contrast agents containing Gd. The purpose of this study was to examine the effects of gadolinium diethylenetriaminepentaacetic acid bismethylamide (Gd[DTPA‐BMA]; Omniscan) as compared with Gd‐DTPA and GdCl3 on the expression and production of cytokines and growth factors by normal human peripheral blood monocytes in vitro and to examine whether conditioned media from Gd‐exposed peripheral blood monocytes could induce a profibrotic phenotype in dermal fibroblasts. Methods Normal human peripheral blood monocytes isolated by Ficoll‐Hypaque gradient centrifugation and plastic adherence were incubated with various concentrations of Gd[DTPA‐BMA], Gd‐DTPA, or GdCl3. Gene expression of interleukins 4, 6, and 13, interferon‐γ, tumor necrosis factor α, transforming growth factor β, connective tissue growth factor, and vascular endothelial growth factor were assessed by real‐time polymerase chain reaction (PCR) analysis. Production and secretion of cytokines and growth factors by Gd compound–exposed monocytes was quantified by enzyme‐linked immunosorbent assay proteome multiplex arrays. The effects of conditioned media from the Gd compound–exposed monocytes on the phenotype of normal human dermal fibroblasts were examined by real‐time PCR and Western blotting. Results The 3 Gd‐containing compounds stimulated the expression and production of numerous cytokines and growth factors by normal human peripheral blood monocytes. Conditioned media from these cells induced a profibrotic phenotype in normal human dermal fibroblasts. Conclusion The 3 Gd‐containing compounds studied induce potent cellular responses in normal human peripheral blood monocytes, which may participate in the development of tissue fibrosis in NSF.

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