Centrality of bone marrow in the severity of gadolinium‐based contrast‐induced systemic fibrosis

Abstract

Systemic fibrosis can be induced in humans with gadolinium-based contrast, and cumulative doses correlate with severity. Bone marrow-derived fibrocytes accumulate in the dermis. Whether target organs liberate chemokines to recruit these fibrocytes or whether fibrocytes are stimulated to home to the affected tissue is unknown. Transgenic (tagged) donor rats were treated with gadolinium-based contrast. Bone marrow was obtained from diseased animals and age-matched controls. Rats with subtotal nephrectomies were lethally irradiated and underwent salvage transplantation with either the contrast-naïve or contrast-exposed bone marrow. Groups were randomly assigned to control or contrast treatment. Contrast treatment led to dermal fibrosis, and this was exacerbated in recipients of contrast-exposed marrow. Fibronectin, C-C chemokine receptors (CCRs)2 and 7, and oxidative stress were all increased in skin from contrast-treated animals-all parameters more severe in recipients of contrast-treated animals. The respective ligands, monocyte chemoattractant protein and C-C motif ligand 19, were both elevated in skin from contrast-treated animals. Coadministration of gadolinium-based contrast and a CCR2 inhibitor reduced the severity of skin disease as well as dermal cellularity. The functional role of chemokines in the effects of gadolinium-based contrast was further confirmed in in situ coculture studies using neutralizing CCR2 antibodies. These data implicate dermal liberation of specific chemokines in the recruitment of circulating bone marrow-derived cells. The disease is augmented by bone marrow exposure to contrast, which explains why multiple exposures correlate with severity.-Drel, V. R., Tan, C., Barnes, J. L., Gorin, Y., Lee, D.-Y., Wagner, B. Centrality of bone marrow in the severity of gadolinium-based contrast-induced systemic fibrosis.

Nephrogenic Systemic Fibrosis Is Mediated by Myeloid C-C Chemokine Receptor 2

“…Similar to what has been described in humans and in our own rat models (Do et al, 2014;Drel et al, 2016;Wagner et al, 2012), there was an increase in dermal cellularity (Figure 1b and c). The nuclei were dense and spindle-shaped, as we have reported in rats (Do et al, 2014;Drel et al, 2016;Wagner et al, 2012). The dermis from contrast-treated animals showed an increase in fibronectin ( Figure 1d).…”

“…The dermis from contrast-treated mice demonstrated an increase in the CD45RO-positive myeloid cells (Figure 3c). We have found that CD163, a marker of alternatively activated macrophages (Swaminathan et al, 2013), is found in the dermis of contrast-treated rats (Drel et al, 2016). In the dermis from the contrast-treated mice, CD163-positive myeloid cells were similarly abundant (Figure 3d).…”

“…MCP-1 and its receptor, the CCR2, are elevated in the skin of contrast-treated rats (Drel et al, 2016). When gadolinium-based contrast-treated rats receive an antagonist of the CCR2, skin fibrosis and dermal cellularity are abrogated (Drel et al, 2016). Therefore, these effectors were examined in the skin of the chimeric mice ( Figure 4).…”

“…This permitted tracing the myeloid lineage of the skin cellularity. As the monocyte chemoattractant protein-1 (MCP-1) and its primary receptor, the C-C chemokine receptor 2 (CCR2), have been implicated in mediating the effects of gadolinium-based contrast agenteinduced fibrosis (Drel et al, 2016), bone marrow transplantation experiments were performed to identify this system as a primary mechanism of the disease.…”

Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats

“…Alternatively, Gd may be preferentially trapped in the bone marrow. 28,30 In our study, the Gd concentration was found to be higher in the femoral bone than in the tested flat bone, the latter being rich in bone marrow. However, we cannot conclude that there is preferential storage in the cortical bone because only femoral epiphyses were sampled.…”