Animal model of sclerotic skin. II. Bleomycin induced scleroderma in genetically mast cell deficient WBB6F1-W/W(V) mice.
OBJECTIVE
Previously, we established a mouse model of scleroderma induced by repeated subcutaneous bleomycin injections. In this model, increased numbers of mast cells were observed in the lesional skin of dermal sclerosis, and degranulation of mast cells was prominent prior to the increase of mast cell numbers. Mast cells have been suggested to play an important role in tissue fibrosis. In this study, we investigated whether dermal sclerosis is also induced by bleomycin administration in genetically mast cell deficient WBB6F1-W/W(V) mice.


METHODS
Bleomycin was subcutaneously injected every day in WBB6F1-W/W(V) and their normal littermate WBB6F1-+/+ mice for 4 weeks, and mice were analyzed for histological sclerosis, mast cell number, plasma histamine level, and hydroxyproline content.


RESULTS
Four weeks' injections of bleomycin effected histological dermal sclerosis in both mast cell deficient and control strains; however, at 1 week, dermal sclerosis was induced only in WBB6F1-+/+ mice. Mast cells gradually increased in number around or on the edge of sclerotic lesions in WBB6F1-+/+ mice, as the dermal sclerosis developed. Hydroxyproline content of the skin of WBB6F1-+/+ mice was higher than that of WBB6F1-W/Wv mice at 1 week, but was not statistically significant. After 2 weeks' treatment with bleomycin, the hydroxyproline content of the skin was similar in both strains. The number of infiltrating macrophages and CD4+ T cells also gradually increased in both strains; however, the difference did not reach significance during the course of bleomycin treatment.


CONCLUSIONS
These results show that mast cell is not necessary for inducing dermal sclerosis by bleomycin, and other types of inflammatory cells such as infiltrating macrophages or T lymphocytes may play a role in triggering induction of dermal sclerosis via fibrogenic cytokines. However, mast cell releasing mediators or cytokines may play a role in accelerating formation of dermal sclerosis, in particular, at an early phase of the sclerotic process, and not merely as a result of sclerosis.
Yamamoto
T
T
Department of Dermatology, Tokyo Medical and Dental University, School of Medicine, Japan.
Takahashi
Y
Y
Takagawa
S
S
Katayama
I
I
Nishioka
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic; D001706:Biopsy; D001761:Bleomycin; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006632:Histamine / Q000097:blood; D006909:Hydroxyproline / Q000032:analysis; D015847:Interleukin-4 / Q000097:blood; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008817:Mice, Mutant Strains; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics*; D012598:Sclerosis; D012867:Skin / Q000737:chemistry / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000903:Antibiotics, Antineoplastic; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D015847:Interleukin-4; D006632:Histamine; D006909:Hydroxyproline