Paine R, Preston A M, Wilcoxen S, Jin H, Siu B B, Morris S B, Reed J A, Ross G, Whitsett J A, Beck J M
Division of Pulmonary and Critical Care Medicine, University of Michigan, and Department of Veterans Affairs Medical Center, Ann Arbor, MI 48105, USA.
J Immunol. 2000 Mar 1;164(5):2602-9. doi: 10.4049/jimmunol.164.5.2602.
Innate immunity plays an important role in pulmonary host defense against Pneumocystis carinii, an important pathogen in individuals with impaired cell-mediated immunity. We investigated the role of GM-CSF in host defense in a model of P. carinii pneumonia induced by intratracheal inoculation of CD4-depleted mice. Lung GM-CSF levels increased progressively during the infection and were significantly greater than those in uninfected controls 3, 4, and 5 wk after inoculation. When GM-CSF gene-targeted mice (GM-/-) depleted of CD4+ cells were inoculated with P. carinii, the intensities of infection and inflammation were increased significantly compared with those in CD4-depleted wild-type mice. In contrast, transgenic expression of GM-CSF directed solely in the lungs of GM-/- mice (using the surfactant protein C promoter) dramatically decreased the intensity of infection and inflammation 4 wk after inoculation. The concentrations of surfactant proteins A and D were greater in both uninfected and infected GM-/- mice compared with those in wild-type controls, suggesting that this component of the innate response was preserved in the GM-/- mice. However, alveolar macrophages (AM) from GM-/- mice demonstrated impaired phagocytosis of purified murine P. carinii organisms in vitro compared with AM from wild-type mice. Similarly, AM production of TNF-alpha in response to P. carinii in vitro was totally absent in AM from GM-/- mice, while GM-CSF-replete mice produced abundant TNF in this setting. Thus, GM-CSF plays a critical role in the inflammatory response to P. carinii in the setting of impaired cell-mediated immunity through effects on AM activation.
固有免疫在肺部抵御卡氏肺孢子虫的宿主防御中发挥重要作用，卡氏肺孢子虫是细胞介导免疫受损个体的一种重要病原体。我们在通过气管内接种使CD4细胞耗竭的小鼠所建立的卡氏肺孢子虫肺炎模型中，研究了粒细胞-巨噬细胞集落刺激因子（GM-CSF）在宿主防御中的作用。在感染过程中，肺组织GM-CSF水平逐渐升高，且在接种后3、4和5周时显著高于未感染的对照小鼠。当给CD4+细胞耗竭的GM-CSF基因敲除小鼠（GM-/-）接种卡氏肺孢子虫时，与CD4细胞耗竭的野生型小鼠相比，感染和炎症的强度显著增加。相反，仅在GM-/-小鼠的肺组织中定向进行GM-CSF的转基因表达（使用表面活性蛋白C启动子），在接种后4周时显著降低了感染和炎症的强度。与野生型对照相比，未感染和感染的GM-/-小鼠中表面活性蛋白A和D的浓度均更高，这表明固有免疫反应的这一组成部分在GM-/-小鼠中得以保留。然而，与野生型小鼠的肺泡巨噬细胞（AM）相比，GM-/-小鼠的AM在体外对纯化的鼠源卡氏肺孢子虫的吞噬作用受损。同样，GM-/-小鼠的AM在体外对卡氏肺孢子虫刺激不产生肿瘤坏死因子-α（TNF-α），而GM-CSF充足的小鼠在这种情况下能产生大量TNF。因此，在细胞介导免疫受损的情况下，GM-CSF通过对AM激活的作用，在对卡氏肺孢子虫的炎症反应中起关键作用。
