ROLE OF PROTEASE IN INFECTION & INFLAMMATION OF COPD

描述（改编自申请人的摘要） 该项目将分析中性粒细胞/单核细胞丝氨酸蛋白酶的作用， 弹性蛋白酶、组织蛋白酶-G和蛋白酶-3及其特异性抑制剂，α- 1-抗胰蛋白酶，尤其是MNEI（单核细胞/中性粒细胞弹性蛋白酶抑制剂）， 感染和炎症。 待评估的假设是， 炎性肺液中蛋白酶过多会导致疾病 不仅通过诱导炎症和损伤， 重要的是通过靶向和破坏先天性抗微生物肺部 防御分子 根据调查人员最近的调查结果， 研究人员假设，一种重要的先天防御分子， 受蛋白酶保护并受MNEI保护的是表面活性剂蛋白-A（SP-A）， 调理素和活化剂，已知可增强 微生物通过常驻肺巨噬细胞传播。 建议在小鼠中进行研究 过度的中性粒细胞/单核细胞蛋白酶活性模型，研究人员 会产生什么样的效果。 Mnei-A def缺陷小鼠将 与野生型小鼠相比， 肺炎链球菌和不可分型流感嗜血杆菌，显著 慢性支气管炎的病原体。 炎症参数（中性粒细胞 内流、游离蛋白酶、SP-A水平、细胞因子、趋化因子）也将被 比较了 使用互补的人类体外系统，研究人员将 比较COPD患者的炎性肺液（BAL上清液）与肺 正常健康的非吸烟者和吸烟者的液体，因为他们能够增强 S的吸收。pneumoniae和H.正常巨噬细胞感染流感病毒。 的 研究人员还将研究外源蛋白酶对细菌生长的影响。 摄取增强活性（包括SP-A）。 阐明弹性蛋白酶的作用， 组织蛋白酶-G和蛋白酶-3在COPD疾病进展中是重要的， 除其他原因外，因为治疗方式现在是可行的， 如果潜在的病理过程是 明白

DESCRIPTION (adapted from the applicants' abstract) The project will analyze the role of the neutrophil/monocyte serine proteases, elastase, cathepsin-G and proteinase-3, and their specific inhibitors, alpha- 1-antitrypsin and especially MNEI (monocyte/neutrophil elastase inhibitor), in infection and inflammation of COPD. The hypothesis to be evaluated is that excess of the proteases in inflammatory lung fluids contributes to disease progression, not only by inducing inflammation and injury, but also importantly by targeting and destroying innate anti-microbial pulmonary defense molecules. Based largely on the investigators recent findings, the investigators hypothesize that an important innate defense molecule targeted by the proteases, and protected by MNEI, is surfactant protein-A (SP-A), an opsonin and activating agent, known to enhance uptake and clearance of microbes by resident pulmonary macrophages. Studies are proposed in a mouse model of excess neutrophil/monocyte protease activity, which the investigators will generate by targeting the mnei gene. Mnei-A def deficient mice will be compared to wildtype mice for their ability to clear pulmonary infections with Streptococcus pneumoniae and nontypeable Haemophilus influenzae, significant infectious agents in chronic bronchitits. Inflammatory parameters (neutrophil influx, free protease, SP-A levels, cytokines, chemokines) will also be compared. Using a complementary human in vitro system, the investigators will compare inflammatory lung fluids (BAL supernatants) of COPD patients with lung fluids of normal healthy non-smokers and smokers, for their ability to enhance uptake of S. pneumoniae and H. influenzae by normal macrophages. The investigators will examine also the effect of exogenous protease on bacterial uptake enhancing activity (including SP-A). Clarifying the role of elastase, cathepsin-G and proteinase-3 in disease progression of COPD is important, among other reasons, because therapeutic modalities are now feasible and could be delivered to the patients if the underlying pathological processes were understood.