Debs R J, Fuchs H J, Philip R, Montgomery A B, Brunette E N, Liggitt D, Patton J S, Shellito J E
Cancer Research Institute, University of California, San Francisco 94143.
J Immunol. 1988 May 15;140(10):3482-8.
The recombinant cytokines IFN-gamma and TNF-alpha stimulate several macrophage-mediated functions important in host defense. However, systemic administration of cytokines may be limited by significant host toxicity. We investigated whether aerosolized cytokines can stimulate alveolar macrophage and blood monocyte function, and whether they induce an inflammatory response in the lungs of normal rats. We found that aerosolized murine rIFN-gamma or recombinant human TNF-alpha increased IL-1 production by both alveolar macrophages and blood monocytes for at least 5 days after administration. Furthermore, murine rIFN-gamma increased the expression of Ia Ag on alveolar macrophages and human rTNF-alpha increased alveolar macrophage- and blood monocyte-mediated tumor lysis. Sequential aerosolization of IFN-gamma and TNF-alpha significantly increased both IL-1 release and Ia expression compared to either cytokine administered alone. Aerosolized human rTNF-alpha achieved lung levels comparable to those produced by an i.v. TNF-alpha dose reported to cause diffuse organ injury and death in rats. However, plasma TNF-alpha levels were several thousand-fold lower after aerosol administration. Aerosolized cytokines did not induce lung edema or an inflammatory cell infiltrate within the airways or alveoli. Aerosolized human rTNF-alpha alone, or murine rIFN-gamma and human rTNF-alpha, induced margination of leukocytes in pulmonary blood vessels 1 day after aerosolization, and a few small foci of pulmonary hemorrhage 5 days later. We conclude that aerosol administration of IFN-gamma or TNF-alpha enhances both pulmonary and systemic monocyte function, and that the combination of IFN-gamma and TNF-alpha produce additive or synergistic effects. Aerosolized cytokines induce only a minimal pulmonary inflammatory response. Aerosolized TNF-alpha produces high cytokine levels in the lung but very low uptake into the circulation.
重组细胞因子γ干扰素（IFN-γ）和肿瘤坏死因子-α（TNF-α）可刺激多种巨噬细胞介导的、对宿主防御至关重要的功能。然而，细胞因子的全身给药可能会受到严重宿主毒性的限制。我们研究了雾化细胞因子是否能刺激肺泡巨噬细胞和血液单核细胞的功能，以及它们是否会在正常大鼠肺部引发炎症反应。我们发现，雾化的鼠源重组IFN-γ或重组人TNF-α给药后至少5天内，可增加肺泡巨噬细胞和血液单核细胞产生白细胞介素-1（IL-1）。此外，鼠源重组IFN-γ可增加肺泡巨噬细胞上Ia抗原的表达，人重组TNF-α可增强肺泡巨噬细胞和血液单核细胞介导的肿瘤溶解作用。与单独给予任何一种细胞因子相比，顺序雾化IFN-γ和TNF-α可显著增加IL-1释放和Ia表达。雾化的人重组TNF-α在肺部达到的水平与静脉注射据报道可导致大鼠弥漫性器官损伤和死亡的TNF-α剂量所产生的水平相当。然而，雾化给药后血浆TNF-α水平要低数千倍。雾化细胞因子未诱导肺水肿或气道或肺泡内的炎症细胞浸润。单独雾化人重组TNF-α，或鼠源重组IFN-γ与人重组TNF-α，在雾化后1天可诱导肺血管中白细胞边缘化，5天后出现一些小的肺出血灶。我们得出结论，雾化给予IFN-γ或TNF-α可增强肺和全身单核细胞功能，且IFN-γ和TNF-α联合使用产生相加或协同作用。雾化细胞因子仅诱导最小程度的肺部炎症反应。雾化TNF-α在肺部产生高细胞因子水平，但进入循环的摄取量非常低。
