Document Detail

The involvement of pro-inflammatory cytokines in nephrogenic systemic fibrosis - a mechanistic hypothesis based on preclinical results from a rat model treated with gadodiamide.
MedLine Citation:
PMID:  19131226     Owner:  NLM     Status:  MEDLINE    
The evidence for the potential involvement of gadolinium-based contrast agents (GBCAs) in the pathomechanism of nephrogenic systemic fibrosis (NSF), a rare but serious disease occurring in patients with severe or end-stage renal failure, has grown due to recent epidemiological and preclinical research. Nevertheless there is still uncertainty with regard to the prevailing patho-physiological processes that may lead to NSF. To examine the potential mechanism of the fibrotic skin changes we applied a recently published rat model of NSF for investigations into serum markers for inflammation. For this purpose male Wistar rats were treated either once, three, or eight times with a daily intravenous injection of 2.5 mmol/kg gadodiamide, the drug substance of the magnetic resonance imaging (MRI) agent Omniscan. Clinical observations, hematology, clinical pathology, histopathology including electron microscopy and gadolinium (Gd) determination in serum, skin, femur and liver tissue, and a multiplexed analysis of 70 protein serum markers were performed. Gd was detectable in the skin, femur, and liver of the gadodiamide-treated rats 6h after the first administration. Macroscopic skin changes, appearing as reddening and early scab formation, were observed in one animal after the third daily administration and affected all animals after 8 daily administrations. Microscopy revealed dermal infiltrations after three administrations, progressing towards inflammatory lesions, ulcerations and crusts. Among the investigated serum marker panel 13 cytokines were significantly (p<0.01) elevated 6 h after the first injection, and eight stayed elevated over all time points: the monocyte chemotactic proteins MCP-1 and MCP-3, the macrophage inflammatory proteins MIP-1beta and MIP-2, the tumor necrosis factor TNF-alpha, the extracellular matrix regulator tissue inhibitor of metalloproteinase type 1 (TIMP-1), the vascular epithelial growth factor (VEGF) and osteopontin. The latter cytokine is of particular interest, since this matrix cellular glycoprotein is involved in the regulation of dystrophic calcification but also plays a role as a chemoattractant for dendritic cells, macrophages and T-lymphocytes, which in turn activate inflammatory pathways. Reflecting the physiological role of osteopontin, we hypothesize that Gd release from the GBCA-complex leads to the formation of insoluble Gd-deposits subsequently eliciting a physiological response similar to that seen during dystrophic calcification, i.e. an up-regulation of osteopontin and chemoattractant cytokines. Concomitant increase in vascular permeability caused by MIP-1, TNF-alpha and VEGF may lead to extravasation of chelated Gd or Gd-deposits. The inherent persistence of the Gd-deposits may subsequently result in an overactivation of pro-inflammatory pathways progressing towards overt skin effects.
T Steger-Hartmann; M Raschke; B Riefke; H Pietsch; M A Sieber; J Walter
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Publication Detail:
Type:  Journal Article     Date:  2009-01-07
Journal Detail:
Title:  Experimental and toxicologic pathology : official journal of the Gesellschaft f??r Toxikologische Pathologie     Volume:  61     ISSN:  1618-1433     ISO Abbreviation:  Exp. Toxicol. Pathol.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-16     Completed Date:  2010-01-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208920     Medline TA:  Exp Toxicol Pathol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  537-52     Citation Subset:  IM    
Nonclinical Drug Safety, Bayer Schering Pharma AG, 13353 Berlin, Germany.
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MeSH Terms
Blood Proteins / analysis
Capillary Permeability / drug effects
Contrast Media / toxicity*
Cytokines / physiology*
Disease Models, Animal
Gadolinium / pharmacokinetics
Gadolinium DTPA / pharmacokinetics,  toxicity*
Kidney / drug effects,  pathology
Nephrogenic Fibrosing Dermopathy / chemically induced*
Osteopontin / physiology
Principal Component Analysis
Rats, Wistar
Skin / drug effects,  pathology
Reg. No./Substance:
0/Blood Proteins; 0/Contrast Media; 0/Cytokines; 106441-73-0/Osteopontin; 122795-43-1/gadodiamide; 7440-54-2/Gadolinium; 80529-93-7/Gadolinium DTPA

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