Gyetko M R, Chen G H, McDonald R A, Goodman R, Huffnagle G B, Wilkinson C C, Fuller J A, Toews G B
Department of Internal Medicine, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA.
J Clin Invest. 1996 Apr 15;97(8):1818-26. doi: 10.1172/JCI118611.
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<0.0007); 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.
尿激酶（uPA）被认为具有蛋白水解活性，可使炎症细胞在募集过程中穿过组织，并且它被认为是一种细胞因子调节剂。由于无法完全且不可逆地消除uPA，以前无法在体内对这些假设进行明确评估。通过开发uPA缺陷型转基因小鼠（uPA-/-），这一限制已被克服。利用这些小鼠，我们评估了uPA在对新型隐球菌（52D菌株）的肺部炎症反应中的重要性。将新型隐球菌接种到uPA-/-小鼠和对照小鼠（uPA+/+）中，并对肺内细胞募集进行定量。测定肺、脾和脑中的菌落形成单位（CFU）数量以评估清除情况，并绘制生存曲线。接种后第21天，与uPA+/+对照相比，uPA-/-小鼠的肺部炎症（CD45+）、CD4+和CD11b/CD18+细胞明显减少（P<0.0007）；uPA-/-小鼠肺部的CFU持续增加，而uPA+/+小鼠的CFU减少（P<0.005）。在生存研究中，19只uPA+/+小鼠中只有3只死亡，而19只uPA-/-小鼠中有15只死亡（P<0.001）。我们已经证明，uPA是对新型隐球菌肺部炎症反应所必需的。缺乏uPA会导致细胞募集不足、感染失控和死亡。
