The Göttingen minipig for assessment of retinoid efficacy in the skin: comparison of results from topically treated animals with results from organ-cultured skin.
Göttingen minipigs were treated topically for 6 d with a novel retinoid (MDI 301) at concentrations ranging from 0.3% to 30% in cream vehicle. Treatment of the minipigs did not adversely affect their health (hematological and necropsy parameters) or produce changes in the skin suggestive of retinoid-induced skin irritation. After killing the animals, skin samples from each treatment site were excised and maintained in organ culture for 6 d. In addition, untreated skin was also maintained in organ culture and treated with MDI 301 (0.1-5 microg/ml). After 3 d, the culture supernatants were collected and analyzed for levels of collagen type I and for matrix metalloproteinases (MMPs). Both skin samples treated in vivo and skin samples exposed to MDI 301 in culture demonstrated increased collagen production. Only slight changes in levels of MMP-2 (gelatinase A) or MMP-9 (gelatinase B) were seen. After 6 d, the organ-cultured skin was fixed in formalin and prepared for histology. The organ-cultured skin was compared to skin that was fixed at killing after in vivo treatment. Epidermal hyperplasia was quantified at various MDI 301 concentrations. In vivo and in vitro treatments showed similar results-although the thickness was not substantially changed on average, there were focal areas of hyperplasia at higher retinoid concentrations. Taken together, these data suggest that MDI 301 enhances collagen production in minipig skin, without irritation. Furthermore, these studies suggest that minipig skin exposed to the retinoid in organ culture is equally predictive as topically treated skin. The in vitro organ culture approach may provide a cost-effective alternative model to that of the intact animal for skin retinoid testing.
Dame
Michael K
MK
Department of Pathology, University of Michigan Medical School, 1301 Catherine St., Spc 5602, Ann Arbor, MI, 48109-5602, USA, mdame@med.umich.edu.
Paruchuri
Tejaswi
T
DaSilva
Marissa
M
Bhagavathula
Narasimharao
N
Ridder
William
W
Varani
James
J
D000287:Administration, Topical; D000818:Animals; D024042:Collagen Type I / Q000096:biosynthesis; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000254:growth & development; D005260:Female; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D009924:Organ Culture Techniques; D012176:Retinoids / Q000008:administration & dosage* / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development*; D013552:Swine; D013556:Swine, Miniature
D024042:Collagen Type I; C488463:MDI 301; D012176:Retinoids; D020778:Matrix Metalloproteinase 2