Roles of Proteases and Protease Inhibitors in Cutaneous Inflammation

1)本项目旨在阐明纤溶酶原激活物、纤溶酶原激活物抑制物、血浆激肽释放酶、组织激肽释放酶以及高、低分子激肽原在皮肤炎症性疾病中的作用，主要集中在银屑病和掌底脓疱病。我们获得了个别报道的某些结果。白念珠菌、红色毛霉菌、犬小孢子菌和申克孢子菌的培养上清液具有趋化活性。层析研究表明，小分子多肽具有趋化活性。与炎性蛋白水解酶活性的关系仍在研究中。3)血栓调节蛋白是一种将凝血酶捕获到内皮表面的调节因子。抗血栓调节蛋白的免疫组织化学研究表明，免疫反应示踪炎症组织中的新生血管。4)应激(热休克)蛋白(HSPs)是遗传上高度保守的分子，即使在微生物和人类之间也具有共同的抗原决定簇。HSP65是从结核分枝杆菌、麻风分枝杆菌等分枝杆菌中分离出来的一种分子质量为65kD的HSP65，已被发现是引起风湿性关节炎、胰岛素依赖型糖尿病和其他自身免疫性改变的共同抗原。我们的初步研究表明，HSP65的循环抗体在脓疱性、红斑性、血管性和银屑病中存在，这些疾病被局地感染理论所解释。关于γ-T淋巴细胞活性和白细胞蛋白水解酶活性的进一步研究正在进行中。5)本项目由此创新了新的方向。

1) This project was initially planned to clarify roles of plasminogen activator, plasminogen activator inhibitor, plasma kallikrein, tissue kallikrein and high molecular weight and low molecular weight kininogens in skin inflammatory disorders, mainly focusing on psoriasis and palmo-plantar pustulosis. We obtained certain results that have been reported individually. Furthermore, the following results, that are more than initial expectation, were yielded.2) Leukocyte chemotactic activity was shown in culture supernatant of Candida albicans, Trichophyton rubrum, Microsporum canis, and Sporotrichum schenkii. Chromatographic investigation revealed that the chemotactic activities are due to low molecular weight polypeptides. Relationship with the activity of inflammatory proteases are still under the investigation.3) Thrombomodulin is a regulatory factor that traps thrombin on the surface of endothelium. Immunohistochemical study with anti-thrombomodulin demonstrated that the immunoreaction traces neovascularization in the inflammatory tissue.4) Stress (heat-shock) proteins (HSPS) are genetically highly conserved molecules that shares common antigen determinants even between microorganisms and humans. HSP with molecular weight of 65 kD (HSP65) originally isolated from mycobacteria, such as M. tuberculosis and M. leprae, have been shown causative common antigen that induces rheumatic arthritis, insulin-dependent diabetes, and other auto-immune alterations. Preliminary investigation by us showed circulating antibody to HSP65 in pustular, erythematous, angitic and psoriatic disorders that are accounted by focal infection theory. Further investigation in relation to gammadeltaT-lymphocyte activity and leukocyte protease activity are in progress.5) New directions are thus innovated through this project.