Matute-Bello Gustavo, Liles W Conrad, Frevert Charles W, Dhanireddy Shireesha, Ballman Kimberly, Wong Venus, Green Richard R, Song Ho Yeong, Witcher Derrick R, Jakubowski Joseph A, Martin Thomas R
Medical Research Service of the Veterans Affairs Puget Sound Health Care System, Seattle, Washington 98108-1597, USA.
J Infect Dis. 2005 Feb 15;191(4):596-606. doi: 10.1086/427261. Epub 2005 Jan 5.
The Fas/FasL system is both proapoptotic and proinflammatory. FasL is inhibited by decoy receptor-3 (DcR3), a naturally occurring decoy receptor. We determined the effects of systemic blockade of the Fas/FasL system by a DcR3 analog (DcR3-a) in mice with pneumococcal pneumonia.
Streptococcus pneumoniae (7.2 x 105 or 1.9 x 107 cfu/mL) was instilled intratracheally into untreated C57Bl/6 mice, C57Bl/6 mice treated with DcR3-a, or Fas-deficient lpr mice, and the mice were studied 48 h later.
After instillation of the lower bacterial dose, disruption of the Fas/FasL system by either DcR3-a or the lpr mutation resulted in improved clearance of bacteria in the lungs (mean +/- SE, 4.6+/-2.1 x 10(6) and 3.5 +/- 1.6 x 10(6) cfu/lung, respectively, vs. 21.9+/-9.3 x 10(6) cfu/lung in untreated C57Bl/6 mice; P<.05) and decreased percentage of polymorphonuclear neutrophils in bronchoalveolar lavage fluid (mean +/- SE, 19.3%+/-9.5% and 20.2%+/-7.8%, respectively, vs. 55.0%+/-12.2% in untreated C57Bl/6 mice; P<.05). These changes were associated with decreased lung concentrations of the proinflammatory cytokines tumor necrosis factor- alpha and macrophage inflammatory protein-2 and with a decrease in apoptotic cells in the alveolar walls.
Blockade of the Fas/FasL system by DcR3-a in the lungs improves clearance of bacteria in mice with pneumococcal pneumonia.
Fas/FasL系统具有促凋亡和促炎作用。FasL可被诱饵受体3（DcR3，一种天然存在的诱饵受体）抑制。我们研究了DcR3类似物（DcR3-a）对肺炎链球菌肺炎小鼠Fas/FasL系统进行全身阻断的效果。
将肺炎链球菌（7.2×10⁵或1.9×10⁷ cfu/mL）经气管内滴注到未处理的C57Bl/6小鼠、用DcR3-a处理的C57Bl/6小鼠或Fas缺陷的lpr小鼠中，48小时后对小鼠进行研究。
滴注较低细菌剂量后，DcR3-a或lpr突变破坏Fas/FasL系统均导致肺内细菌清除改善（平均±标准误，分别为4.6±2.1×10⁶和3.5±1.6×10⁶ cfu/肺，而未处理的C57Bl/6小鼠为21.9±9.3×10⁶ cfu/肺；P<0.05），支气管肺泡灌洗液中多形核中性粒细胞百分比降低（平均±标准误，分别为19.3%±9.5%和20.2%±7.8%，而未处理的C57Bl/6小鼠为55.0%±12.2%；P<0.05）。这些变化与促炎细胞因子肿瘤坏死因子-α和巨噬细胞炎性蛋白-2的肺内浓度降低以及肺泡壁凋亡细胞减少有关。
肺内用DcR3-a阻断Fas/FasL系统可改善肺炎链球菌肺炎小鼠的细菌清除。
