title: 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.
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA;
authors.forename: Viktor R
authors.initials: VR
authors.lastname: Drel
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA;
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; South Texas Veterans Health Care System, San Antonio,Texas, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA;
authors.forename: Yves
authors.initials: Y
authors.lastname: Gorin
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA;
authors.forename: Doug-Yoon
authors.initials: DY
authors.lastname: Lee
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; South Texas Veterans Health Care System, San Antonio,Texas, USA wagnerb@uthscsa.edu.
authors.forename: Brent
authors.initials: B
authors.lastname: Wagner
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D003287:Contrast Media / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D019786:Gadolinium DTPA / Q000009:adverse effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D054989:Nephrogenic Fibrosing Dermopathy / Q000139:chemically induced* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; C515336:Ccr2 protein, rat; D003287:Contrast Media; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; C064925:gadodiamide; D051547:Heme Oxygenase-1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D019786:Gadolinium DTPA
keywords: CCR2; NADPH oxidase; chemokine CCL2; nephrogenic fibrosing dermopathy; skin diseases