cPLA2介导溶酶体膜通透化所致的细胞焦亡在随意皮瓣缺血坏死中的作用及机制研究

超长随意皮瓣远端易发生缺血坏死，临床上尚缺乏有效的防治方案。前期发现随意皮瓣远端发生细胞焦亡，而焦亡所起的作用不得而知。本研究将明确焦亡在随意皮瓣远端缺血坏死中的作用。为阐明缺血皮瓣中细胞焦亡激活的机制，本研究将验证缺血随意皮瓣中，细胞溶酶体外漏的组织蛋白酶B（CTSB）诱导细胞焦亡的激活。有报道称，胞浆型磷脂酶A2（cPLA2）介导的溶酶体膜通透化，能导致其腔内组织蛋白酶渗出。前期发现缺血随意皮瓣中cPLA2的表达，活性及其产物水平显著增加。本研究将证明在随意皮瓣远端缺血坏死中，cPLA2介导溶酶体膜通透化，导致CTSB从溶酶体腔内渗出，以引发细胞焦亡。并阐明缺血随意皮瓣中cPLA2活性，受细胞内12/15-LOX/Ca2+及12/15-LOX/p38MAPK信号通路调控。本研究旨在阐释随意皮瓣缺血坏死中细胞焦亡的病理机制；并提出通过调控cPLA2抑制焦亡，促进超长随意皮瓣存活的新策略。

The distal portion of ultra-long random skin flap is prone to ischemic necrosis. However, there is no effective prevention and treatment in clinic. It was found in our preliminary experiment that pyroptosis occured in the distal portion of random skin flap, but the role of pyroptosis was unknown. Therefore, we will clarify the functions of pyroptosis in the ischemic necrosis of random skin flap. To further elucidate the mechanisms of pyroptosis activation in the ischemic flap, our study will verify that cathepsin B (CTSB) leakage from lysosome can induce pyroptosis activation in the flap. It was reported that cytoplasmic phospholipase A2 (cPLA2) mediates lysosomal membrane permeability, which can lead to cathepsin leakage from lysosome. Our preliminary studies showed that the expression, activity and production level of cPLA2 were increased in the ishemic flap. So in the study, we will demonstrate that cPLA2 mediates lysosomal membrane permeability, which leads to CTSB leakage from lysosome, then induces pyroptosis in the distal portion of random skin flap. Furthermore, we will clarify that the activity of cPLA2 is regulated by 12/15-LOX/ Ca2+ and 12/15-LOX/ p38MAPK signaling pathways. The purpose of this study is to elucidate the pathological mechanism of pyroptosis in the ischemic necrosis of random skin flap, and to propose a new strategy of regulating cPLA2 to inhibit pyroptosis and consequencely promote the survival of ultra-long random skin flap.