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Enhanced
Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction
of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro |
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Yoshikiyo Akasaka, Yukio Ishikawa, Ichiro Ono, Kazuko Fujita, Takao Masuda,
Noriko Asuwa, Kiyoshi Inuzuka, Hideko Kiguchi, and Toshiharu Ishii
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From
the Second Department of Pathology (YA, YI, TM, HK, TI), School of Medicine,
Toho University, Tokyo; the Departments of Plastic and Reconstructive Surgery
(KI), and Pathology (NA), Hachioji Medical Center, Tokyo Medical College,
Tokyo; Komae Branch, Bio-Science Department, Abiko Research Laboratory,
Central Research Institute of Electric Power Industry (KF), and the Department
of Dermatology (IO), Fukushima Medical College, Fukushima, Japan |
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SUMMARY: Recent studies have suggested that the regulation
of apoptosis during wound healing is important in scar establishment and
development of pathological scarring. To examine the phenomenon of apoptosis
and its involvement in the process of pathological scarring, we immunohistochemically
quantified differential levels of expression of caspase-3 and -2, which
are activated during apoptosis in vitro, in surgical resected scar tissues.
We divided 33 cases of normally healed flat scars and 18 cases of pathological
scars (15 cases of hypertrophic scars and 3 cases of keloid) into three
groups (S = < 10 months' duration; S2 = 10 to 40 months' duration; and
S3 = > 40 months' duration) according to the duration of scar. In all
three groups examined, the semiquantitative scores for caspase-3 staining
were significantly higher for the combination of hypertrophic scars and
keloid as a group compared with normally healed flat scars, suggesting reduced
cell survival and increased apoptotic cell death in hypertrophic scars and
keloid. Apoptosis and caspase proteolytic activities were examined in vitro
using two flat scar-derived fibroblast lines (FSFB-1 and -2) and two keloid-derived
fibroblast lines (KFB-1 and -2). After 24 hours of serum deprivation, apoptotic
cells were significantly increased in both KFB lines, whereas serum deprivation
of FSFB-1 cells did not result in a significant increase in apoptotic cell
number. After serum deprivation, significant increases in caspase-3 proteolytic
activities were detected in both KFB lines compared with both FSFB lines.
In contrast, no significant differences with caspase-8 activity were observed
between similarly treated KFB and FSFB lines. Furthermore, serum deprivation-induced
apoptosis of KFB-2 cells was significantly inhibited by the caspase-3 inhibitor
Ac-Asp-Glu-Val-Asp-fluoromethyl ketone (DEVD-FMK), indicating that caspase-3
is important for serum deprivation-induced apoptosis in KFB-2 cells. Considering
the role of caspase-3 as a key effector molecule inthe execution of apoptotic
stimuli, our results suggested that enhanced expression of caspase-3 in
hypertrophic scars and keloid induces apoptosis of fibroblasts, which may
play a role in the process of pathological scarring. (Lab Invest 2000,
80: 345-357) |
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