Roles of Proteases and Protease Inhibitors in Cutaneous Inflammation

1)该项目最初计划阐明纤溶酶原激活剂、纤溶酶原激活剂抑制剂、血浆激肽释放酶、组织激肽释放酶以及高分子量和低分子量激肽原在皮肤炎症性疾病中的作用，主要关注银屑病和掌跖脓疱病。我们获得了一些已经单独报告的结果。2）白念珠菌、红色毛癣菌、犬小孢子菌和申克孢子丝菌培养上清均具有白细胞趋化活性。色谱研究表明，趋化活性是由于低分子量的多肽。血栓调节蛋白（Thrombomodulin）是一种将凝血酶捕获在内皮细胞表面的调节因子。抗血栓调节蛋白的免疫组化研究表明，免疫反应跟踪炎症组织中的新血管形成。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。HSP 65分子量为65 kD，最初从分枝杆菌中分离，如M.结核和M.麻风是诱发风湿性关节炎、胰岛素依赖型糖尿病和其它自身免疫改变致病性共同抗原。我们的初步研究表明，在脓疱性、肉芽肿性、血管炎性和银屑病性疾病中存在HSP 65的循环抗体，这些疾病都可以用局灶性感染理论来解释。对γ δ T淋巴细胞活性和白细胞蛋白酶活性的进一步研究正在进行中。5）通过本项目创新了新的方向。

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.