title: Nephrogenic systemic fibrosis: evidence for oxidative stress and bone marrow-derived fibrocytes in skin, liver, and heart lesions using a 5/6 nephrectomy rodent model.
abstract: Nephrogenic systemic fibrosis (NSF) is associated with gadolinium-based magnetic resonance imaging (MRI) contrast exposure in the setting of acute or chronic renal compromise. It has been proposed that circulating fibrocytes mediate the disease. A study was conducted to determine whether bone marrow-derived fibroblast precursors are involved in contributing to organ fibrosis in MRI contrast-treated rodents with renal insufficiency. Rats status post 5/6 nephrectomy underwent bone marrow transplant from human placental alkaline phosphatase (hPAP)-expressing donors. After engraftment, animals were treated with gadolinium-based MRI contrast (2.5 mmol/kg IP), during weekdays for 4 weeks, or an equivalent volume of normal saline. Dermal cellularity in the contrast-treated group was fourfold that of control. Skin cells from the contrast-treated group demonstrated greater hPAP expression with co-expression of pro-collagen I and α-smooth muscle actin-positive stress fibers. Donor and host cells expressed CD34. Dihydroethidium staining of skin was greater in the contrast-treated animals, indicating oxidative stress. This was abrogated when the animals were co-administered the superoxide dismutase mimetic tempol. In conclusion, a bone marrow-derived cell population is increased in the dermis of MRI contrast-treated rodents. The cell markers are consistent with fibrocytes mediating the disease. These changes correlate with oxidative stress and expression of Nox4, suggestive of a novel therapeutic target. Elucidation of the mechanisms of MRI contrast-induced fibrosis may aid in discovering therapies to this devastating disease.
authors.affiliation: VA Research, South Texas Veterans Health Care System, University of Texas Health Science Center at San Antonio, TX 78229, USA. wagnerb@uthscsa.edu
authors.forename: Brent
authors.initials: B
authors.lastname: Wagner
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.forename: Seema
authors.initials: S
authors.lastname: Ahuja
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Davis
authors.forename: Yves
authors.initials: Y
authors.lastname: Gorin
authors.forename: Fabio
authors.initials: F
authors.lastname: Jimenez
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001853:Bone Marrow / Q000473:pathology*; D024042:Collagen Type I / Q000378:metabolism; D003287:Contrast Media / Q000009:adverse effects; D020405:Dermis / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D026122:Factor XIIIa / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D009206:Myocardium / Q000473:pathology*; D009392:Nephrectomy; D054989:Nephrogenic Fibrosing Dermopathy / Q000378:metabolism / Q000473:pathology*; D009929:Organ Size; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D012885:Skinfold Thickness; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D024042:Collagen Type I; D003287:Contrast Media; D026122:Factor XIIIa; D017382:Reactive Oxygen Species; C067980:CD68 antigen, human; D000097382:CD68 Molecule