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

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 GdCl 3 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 GdCl 3 . Gene expression of interleukins 4, 6, and 13, interferon-␥, tumor necrosis factor ␣, transforming growth factor ␤, 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.

Mechanism of NSF: New evidence challenging the prevailing theory

“…3. The occurrence of NSF in temporal proximity to inflammatory and thrombotic episodes in affected patients (9,44) suggests that macrophages and inflammatory cells may have been primed by these events and, thus, capable of an enhanced or exaggerated response to noxious agents accords with the observations that monocytes and macrophages can be directly stimulated by GBCA in vitro (38,39). 4.…”

“…Since variable sensitivity of peripheral blood monocytes to stimulation was observed by Wermuth et al (38), such heterogeneity in responsiveness may be one factor that could explain the relatively infrequent occurrence of NSF among the large population of patients with renal insufficiency exposed to GBCA. Another possibility to be considered is that cells derived from patients with renal insufficiency who develop NSF may have a more pronounced response to GBCA than those derived from normal patients.…”

“…These observations are extremely important, since Wermuth et al (38) also demonstrated that conditioned media isolated from GBCA-exposed PBMC caused cultured human dermal fibroblasts to increase expression of extracellular matrix proteins and a-SMA indicating their conversion into myofibroblasts (38). Since these studies show that it is possible for products of inflammatory cells to induce a fibrotic phenotype in normal dermal human fibroblasts in vitro, it is plausible that GBCA, under certain conditions, could stimulate inflammatory cells in blood to secrete the mediators essential to the development of NSF.…”

“…Wermuth et al (38) have shown that chelated Gd (gadodiamide [Gd 3þ -DTPA-BMA, Omniscan] and gadopentetate dimeglumine [Gd 3þ -DTPA, Magnevist]) can directly stimulate human monocytes and macrophages to express and release fibrotic cytokines and growth factors that are capable of initiating and supporting the tissue fibrosis that is characteristic of NSF. In these studies human peripheral blood monocytes were exposed to varying concentrations of GBCA or GdCl 3 over 24 hours.…”

Gadolinium‐based contrast agents and NSF: Evidence from animal experience

“…The researchers observed an inverse relationship between compound stability and concentration required to stimulate fibroblast responses (25). An in vitro activation of fibroblasts and peripheral blood monocytes by GBCAs have also been reported (26,27).…”