Division of Surgical Research, Department of Surgery, Rhode Island Hospital/Alpert School of Medicine at Brown University, Providence, Rhode Island 02903, USA.
Shock. 2012 Jun;37(6):611-20. doi: 10.1097/SHK.0b013e318254fa6a.
Tumor necrosis factor α (TNF-α) has been reported to be a key component of the functional priming, of both myeloid and nonmyeloid cells, that is thought to contribute to the lung's increased susceptibility to injury following shock. Not surprisingly, we found that mice deficient in TNF-α exhibited reduced acute lung injury (ALI) resultant from the combined insults of hemorrhagic shock and sepsis. However, we found that when we adoptively transferred neutrophils from mice expressing TNF-α to neutrophil-depleted mice that lacked TNF-α, they were not able to serve as priming stimulus for the development of ALI. Based on these findings, we proposed that resident lung tissue cells mediate TNF-α priming. To begin to unravel the complex signaling pathway of various resident lung tissue cells in TNF-α-induced priming, we compared the effect of local (intratracheal [i.t.]) versus systemic [intravenous (i.v.)] delivery of TNF-α small interference (siRNA). We hypothesized that alternately suppressing expression of TNF-α in lung endothelial (i.v.) or epithelial (i.t.) cells would produce a differential effect in shock-induced ALI. We found that when in vivo siRNA i.t. or i.v. against TNF-α was administered to C57/BL6 mice at 2 h after hemorrhage, 24 h before septic challenge, that systemic/i.v., but not i.t., delivery of TNF-α siRNA following hemorrhage priming significantly reduces expression of indices of ALI compared with controls. These findings suggest that an absence of local lung tissue TNF-α significantly reduces lung tissue injury following hemorrhage priming for ALI and that pulmonary endothelial and/or other possible vascular resident cells, not epithelial cells, play a greater role in mediating the TNF-α priming response in a mouse model of hemorrhage/sepsis-induced ALI.
肿瘤坏死因子-α（TNF-α）已被报道是功能性启动的关键组成部分，包括髓系和非髓系细胞，这被认为有助于休克后肺对损伤的易感性增加。毫不奇怪，我们发现缺乏 TNF-α 的小鼠表现出由出血性休克和败血症联合打击引起的急性肺损伤（ALI）减少。然而，我们发现，当我们从表达 TNF-α的小鼠中过继转移中性粒细胞到缺乏 TNF-α的中性粒细胞耗竭小鼠中时，它们不能作为 ALI 发展的启动刺激。基于这些发现，我们提出驻留肺组织细胞介导 TNF-α启动。为了开始阐明驻留肺组织细胞中 TNF-α诱导启动的复杂信号通路，我们比较了局部（气管内 [i.t.]）与全身（静脉内 [i.v.]）给予 TNF-α 小干扰（siRNA）的效果。我们假设交替抑制肺内皮细胞（i.v.）或上皮细胞（i.t.）中 TNF-α 的表达会在休克诱导的 ALI 中产生不同的效果。我们发现，当在出血后 2 小时、败血症攻击前 24 小时，将体内 i.t. 或 i.v. 的 TNF-α siRNA 给予 C57/BL6 小鼠时，全身/i.v.，而不是 i.t.，给予 TNF-α siRNA 可显著降低与对照组相比，ALI 的指标表达。这些发现表明，局部肺组织 TNF-α 的缺失可显著降低 ALI 出血性启动后的肺组织损伤，并且肺内皮细胞和/或其他可能的血管驻留细胞，而不是上皮细胞，在介导小鼠出血性休克/败血症诱导的 ALI 中的 TNF-α 启动反应中起更大作用。
