MODULATION OF EXTRACELLULAR NEUTROPHIL ELASTASE ACTIVITY

炎症过程中中性粒细胞释放的弹性蛋白酶与 在许多疾病过程中组织损伤的发病机理中， 包括肺气肿 细胞外中性粒细胞的控制 弹性蛋白酶活性取决于：1）蛋白酶抑制剂（主要是 α 1-蛋白酶抑制剂和α 2-巨球蛋白）;和2）相互作用 单核吞噬细胞系统。 因为α 2-巨球蛋白 在下呼吸道中不存在或以低浓度存在， 间隙空间，控制这些位置释放的弹性蛋白酶将 预期依赖于α 1-蛋白酶抑制剂的抑制作用， 活性酶与肺泡（和间质）巨噬细胞的结合。 我们 氧化剂对α 1-蛋白酶抑制剂失活假设 （包括香烟烟雾中的氧化剂和活性氧化剂） 增加了炎症期间组织损伤的风险， 单核巨噬细胞系统承担更大的重要性 抗弹性蛋白酶防御 因此，我们建议：1）进一步研究在 肺泡巨噬细胞对中性粒细胞弹性蛋白酶的体外结合和内化 关于巨噬细胞受体的性质， 弹性蛋白酶，内化酶活性，细胞内 相对于巨噬细胞抑制剂的内化酶的定位 弹性蛋白酶和促进弹性蛋白酶先前释放的条件 由巨噬细胞内化;和2）量化氧化的部分 α 1蛋白酶抑制剂在血浆和支气管肺泡中的初步研究 从人类不吸烟者和吸烟者的灌洗液中，并将 结果与吸烟史、呼吸道症状和症状程度有关 损伤 我们预计，对控制的更好的洞察力 在健康和疾病中释放中性粒细胞弹性蛋白酶活性， 从这些研究将有助于制定战略， 在肺气肿等疾病中的蛋白水解组织损伤。

Elastase released from neutrophils during inflammation has been implicated in the pathogenesis of tissue injury in a number of disease processes, including pulmonary emphysema. Control of extracellular neutrophil elastase activity depends upon: 1) proteinase inhibitors (primarily alpha1-proteinase inhibitor and alpha2-macroglobulin); and 2) interaction with the mononuclear phagocyte system. Because alpha2-macroglobulin is absent or present in low concentrations in the lower respiratory tract and interstitial space, control of released elastase in these locations would be expected to depend upon inhibition by alpha1-proteinase inhibitor and binding of active enzyme to alveolar (and interstitial) macrophages. We hypothesize that inactivation of alpha1-proteinase inhibitor by oxidants (including oxidants from cigarette smoke and activated neutrophilis) increases the risk of tissue injury during inflammation, and also causes the mononuclear phagocyte system to assume greater importance in antielastase defenses. We therefore propose to: 1) Further study the in vitro binding and internalization of neutrophil elastase by alveolar macrophages with regard to the nature of the macrophage receptor for elastase, the enzymatic activity of internalized enzyme, the intracellular localization of internalized enzyme relative to the macrophage inhibitor of elastase, and conditions which promote release of elastase previously internalized by macrophages; and 2) quantify the fraction of oxidized alpha1-proteinase inhibitor in a pilot study in plasma and bronchoalveolar lavage fluid from human nonsmokers and cigarette smokers, and relate the results to smoking history, respiratory symptoms; and degree of ventilatory impairment. We anticipate that the improved insight into control of released neutrophil elastase activity in health and disease which results from these studies will be helpful in developing strategies for limitation of proteolytic tissue injury in diseases such as pulmonary emphysema.