Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans - A murine transgenic model
Urokinase is required for the pulmonary inflammatory response to Cryptococcus neoformans - A murine transgenic model
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DOI：
10.1172/jci118611
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发表时间：
1996-04-15
影响因子：
15.9
通讯作者：
Toews, GB
中科院分区：
文献类型：
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作者：
Gyetko, MR;Chen, GH;Toews, GB
据推测，尿激酶 (uPA) 提供蛋白水解活性，使炎症细胞在募集过程中能够穿过组织，并且它被认为是一种细胞因子调节剂。由于 uPA 无法完全且不可逆地消除，因此在体内对这些假设进行明确评估以前是不可能的。通过开发 uPA 缺陷转基因小鼠 (uPA(-/-)) 克服了这一限制。使用这些小鼠，我们评估了 uPA 在新型隐球菌（菌株 52D）肺部炎症反应中的重要性。将新型隐球菌接种到 uPA(-/-) 和对照小鼠 (uPA(+/+)) 中，对肺部的细胞募集进行定量，测定肺、脾和脑中的 CFU 数量以评估清除率，并生成生存曲线。 接种后第 21 天，uPA(-/-) 小鼠的肺部炎症 (CD45(+))、CD4(+) 和肺部炎症明显减少。 CD11b/CD18(+) 细胞与 uPA(+/+) 对照相比 (P < 0.007)； uPA(-/-) 小鼠的肺部 CFU 持续增加，而 uPA(+/-) 小鼠的 CFU 减少 (P < 0.005)，在生存研究中，只有 3/19 uPA(+/+) 小鼠死亡，而 15/19 uPA(-/-) 小鼠死亡 (P < 0.001)。导致细胞募集不足、感染失控和死亡。
Urokinase (uPA) is hypothesized to provide proteolytic activity enabling inflammatory cells to traverse tissues during recruitment, and it is implicated as a cytokine modulator. Definitive evaluation of these hypotheses in vivo has previously been impossible because uPA could not completely and irreversibly be eliminated, This limitation has been overcome through the development of uPA-deficient transgenic mice (uPA(-/-)). Using these mice, we evaluated the importance of uPA in the pulmonary inflammatory response to Cryptococcus neoformans (strain 52D). C. neoformans was inoculated into uPA(-/-) and control mice (uPA(+/+)), and cell recruitment to the lungs was quantitated, The number of CFU in lung, spleen and brain was determined to assess clearance, and survival curves were generated, By day 21 after inoculation, uPA(-/-) mice had markedly fewer pulmonary inflammatory (CD45(+)), CD4(+), and CD11b/CD18(+) cells compared with uPA(+/+) controls (P < 0.007); pulmonary CFUs in the uPA(-/-) mice continued to increase, whereas CFUs diminished in uPA(+/+) mice (P < 0.005), In survival studies, only 3/19 uPA(+/+) mice died, whereas 15/19 uPA(-/-) mice died (P < 0.001), We have demonstrated that uPA is required for a pulmonary inflammatory response to C. neoformans, Lack of uPA results in inadequate cellular recruitment, uncontrolled infection, and death.