Enhanced Expression of Caspase-3 in Hypertrophic Scars and Keloid: Induction of Caspase-3 and Apoptosis in Keloid Fibroblasts In Vitro

Abstract

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 (S1 ϭ Ͻ10 months' duration; S2 ϭ 10 to 40 months' duration; and S3 ϭ Ͼ40 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 in the 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).

Functional and morphological evaluation of a low‐weight, monofilament polypropylene mesh for hernia repair

“…However, the high level of the cytoprotective HSP 70 12 after 90 days indicates a permanent cell stress even at the interface of the LW mesh. Compared to investigations at scars 13,14 the measurements of the apoptosis and proliferation imply a considerably increased cell-turnover process in the HW group, whereas the LW mesh indicated almost physiological levels. In accordance with the present data, the persistently increased remodeling and cell turnover has been proved recently in human explanted heavyweight polypropylene mesh samples.…”

Antirestenotic Effects of a Locally Delivered Caspase Inhibitor in a Balloon Injury Model

“…Enhanced expression of activated caspase-3 in hypertrophied scars and keloid has been shown to induce apoptosis in fibroblasts. 23 Naturally occurring viral caspase inhibitors have the ability to inhibit caspase activation and activity, thus averting apoptotic cell death. Synthetic caspase inhibitors, such as ZVAD-fmk, applied directly to infarcting rat myocardium have been shown to limit infarct size.…”

Oxidative damage and nuclear factor erythroid 2-related factor 2 protein expression in normal skin and keloid tissue

“…Jiménez et al 38 indicated that c-myc and rho-p21 are potent inducers of apoptosis, whereas Bcl-2, v-abl, E1B, and ras prevent activation of the apoptotic pathway in fibroblasts. Akasaka et al 36 also reported that the increased expression of caspase-3 in keloids can induce apoptosis in fibroblasts. Since ROS production can induce apoptosis, we hypothesized that Nrf2 may be involved in this process.…”

“…Desmoulière et al 33 have shown that the number of apoptotic cells sharply increases as the wound closes, suggesting that apoptosis is involved in the progressive transformation of granulation tissue into scar. A few studies have reported increased apoptosis in keloid fibroblasts 5,36 . Akasaka et al 37 reported increased apoptosis in keloid fibroblast cells compared to normal fibroblasts and hypertrophic scars.…”