Excessive tumor necrosis factor (TNF) is known to cause significant pathology. Paradoxically, deficiency in TNF (TNF^−/−) also caused substantial pathology during respiratory ectromelia virus (ECTV) infection, a surrogate model for smallpox. TNF^−/− mice succumbed to fulminant disease whereas wild-type mice, and those engineered to express only transmembrane TNF (mTNF), fully recovered. TNF deficiency did not affect viral load or leukocyte recruitment but caused severe lung pathology and excessive production of the cytokines interleukin (IL)-6, IL-10, transforming growth factor beta (TGF-β), and interferon gamma (IFN-γ). Short-term blockade of these cytokines significantly reduced lung pathology in TNF^−/− mice concomitant with induction of protein inhibitor of activated STAT3 (PIAS3) and/or suppressor of cytokine signaling 3 (SOCS3), factors that inhibit STAT3 activation. Consequently, inhibition of STAT3 activation with an inhibitor reduced lung pathology. Long-term neutralization of IL-6 or TGF-β protected TNF^−/− mice from an otherwise lethal infection. Thus, mTNF alone is necessary and sufficient to regulate lung inflammation but it has no direct antiviral activity against ECTV. The data indicate that targeting specific cytokines or cytokine-signaling pathways to reduce or ameliorate lung inflammation during respiratory viral infections is possible but that the timing and duration of the interventive measure are critical.

已知过多的肿瘤坏死因子（TNF）会导致严重的病理。矛盾的是，TNF（TNF ^-/-）的缺乏也导致呼吸道直肠菌病毒（ECTV）感染（天花的替代模型）期间出现了严重的病理。TNF ^-/-小鼠死于暴发性疾病，而野生型小鼠和仅表达跨膜TNF（mTNF）的小鼠完全康复。TNF缺乏症不会影响病毒载量或白细胞募集，但会导致严重的肺部疾病以及细胞因子白介素（IL）-6，IL-10，转化生长因子β（TGF-β）和干扰素γ（IFN-γ）的过量产生。短期阻断这些细胞因子可显着降低TNF ^-/-的肺部病理诱导STAT3活化的蛋白抑制剂（PIAS3）和/或细胞因子信号传导抑制因子3（SOCS3）的小鼠，它们是抑制STAT3激活的因子。因此，用抑制剂抑制STAT3激活可减少肺部病理。IL-6或TGF-β的长期中和可保护TNF ^-/-小鼠免受致命的感染。因此，单独的mTNF对调节肺部炎症是必要和充分的，但对ECTV没有直接的抗病毒活性。数据表明，针对特定的细胞因子或细胞因子信号通路减少或改善呼吸道病毒感染期间的肺部炎症可能是可行的，但是干预措施的时机和持续时间至关重要。