Anti-inflammatory effects of mutant forms of secretory leukocyte protease inhibitor

作     者：Mulligan, MS Lentsch, AB Huber-Lang, M Guo, RF Sarma, V Wright, CD Ulich, TR Ward, PA 

作者机构：Univ Michigan Sch Med Dept Pathol Ann Arbor MI 48109 USA Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA Univ Louisville Sch Med Dept Surg Louisville KY 40292 USA Amgen Inc Thousand Oaks CA 91320 USA 

出 版 物：《AMERICAN JOURNAL OF PATHOLOGY》 (美国病理学杂志)

年 卷 期：2000年第156卷第3期

页      面：1033-1039页

核心收录：

学科分类：1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：NHLBI NIH HHS [P01-HL-31963, P01 HL031963] Funding Source: Medline NIGMS NIH HHS [GM-29507, R01 GM029507, R37 GM029507] Funding Source: Medline 

主　　题：急性病 肺泡炎 外源性变应性/代谢 肺泡炎 外源性变应性/病理生理学 氨基酸取代 消炎药 抗原抗体复合物/免疫学 毛细血管通透性/生理学 疾病模型 动物 免疫球蛋白G/免疫学 肺/血液供给 肺/代谢 肺/病理学 诱变 定点 NF-κB/代谢 中性白细胞浸润/生理学 蛋白酶抑制蛋白质类 分泌 蛋白质类/遗传学 蛋白质类/生理学 大鼠 Long-Evans 分泌型白细胞蛋白酶抑制因子 丝氨酸蛋白酶抑制剂/遗传学 丝氨酸蛋白酶抑制剂/生理学 无特异性病原体有机物 动物 男(雄)性 大鼠 

摘      要：The secretory leukocyte protease inhibitor (SLPI) is found in a variety of secreted fluids in mammals and is a known inhibitor of serine proteases. Wild-type (WT) SLPI has recently been shown to block nuclear factor kappa B (NF-kappa B) activation in rat lungs and to interfere with the ensuing inflammatory response and recruitment of neutrophils after an intrapulmonary deposition of IgG immune complexes. In this study, WT SLPI and SLPI mutants with various degrees of protease-inhibitory capacity (for trypsin, chymotrypsin, and elastase) were evaluated for their ability to suppress the lung-vascular leak, neutrophil accumulation, and NF-kappa B activation in the lung inflammatory model The SLPI mutant with Gly(72) (replacing Leu(72)) lost its ability to block in vivo activation of NF-kappa B, as well as its ability to suppress the lung vascular leak and neutrophil recruitment. The Phe(72) and Gly(20) mutants were as effective as the WT SLPI in suppressing NF-kappa B activation and neutrophil recruitment. The Lys(72) mutant had the most suppressive effects of the lung vascular leak and for neutrophil recruitment into the lung. The in vivo suppressive effects of SLPI mutants on lung vascular permeability, neutrophil recruitment, and NF-kappa B activation appear to be most closely related to their trypsin-inhibiting activity. These data suggest that the suppressive effects of SLPI on the intrapulmonary activation of NF-kappa B and neutrophil recruitment into the lung may be linked to their antiprotease activity, directed, perhaps, at the intracellular proteases.