期刊
INVESTIGATIVE RADIOLOGY
卷 45, 期 1, 页码 42-48出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/RLI.0b013e3181bf95eb
关键词
collagenolytic activity; gadolinium-based contrast agent (GBCA); matrix metalloproteinase 1 (MMP-1); nephrogenic systemic fibrosis (NSF); tissue inhibitor of metalloproteinases-1 (TIMP-1)
资金
- National Institutes of Health, Bethesda, MD [CA 140760, GM 77724, GM 80779]
- NATIONAL CANCER INSTITUTE [R21CA140760] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R43GM077724, R44GM077724, R43GM080779] Funding Source: NIH RePORTER
Objective: Human skin produces increased amounts of matrix metalloproteinase-1 (MMP-1) when exposed in organ culture to Omniscan, one of the gadolinium-based MRI contrast agents (GBCA). MMP-1, by virtue of its ability to degrade structural collagen, contributes to collagen turnover in the skin. The objective of the present study was to determine whether collagenolytic activity was concomitantly tip-regulated with increased enzyme. Materials and Methods: Skin biopsies from normal volunteers were exposed in organ culture to Omniscan. Organ culture fluids obtained from control and treated skin were examined for ability to degrade type I collagen. The same culture fluids were examined for levels of MMP- 1, tissue inhibitor of metallproteinases-1 (TIMP-1), and complexes of MMP-1 arid TIMP-1. Results: Although MMP-1 was increased in culture fluid from Omniscan-treated skin, there was no increase in collagenolytic activity. In fact, collagenolytic activity declined. Increased production of TIMP-1 was also observed in Omniscan-treated skin, and the absolute amount of TIMP-1 was greater than the amount of MMP-1. Virtually all of the MMP- I was present in MMP-1-TIMP-1 complexes, but the majority of TIMP-1 was not associated with MMP-1. When human dermal fibroblasts were exposed to TIMP-1 (up to 250 ng/mL), no increase in proliferation was observed, but an increase in collagen deposition into the cell layer was seen. Conclusion: Gadolinium-based MRI contrast agent exposure has recently been linked to a fibrotic skin condition in patients with impaired kidney function. The mechanism is unknown. The increase in TIMP-1 production and concomitant reduction in collagenolytic activity demonstrated here could result in decreased collagen turnover and increased deposition of collagen in lesional skin.
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