Department of Surgery, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan.
Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Cytokine. 2013 Jul;63(1):58-66. doi: 10.1016/j.cyto.2013.04.002. Epub 2013 Apr 25.
Tumor necrosis factor (TNFα) is a proinflammatory cytokine and has been a target for intervention in human sepsis. However, inhibition of TNF-α with a high dose of a TNF-receptor fusion protein in patients with septic shock worsened patient survival. This study was designed to investigate whether blocking TNF-α enhances mortality in infected burn mice through the induction of IL-1β.
WT or Tnfrsf1a(-/-) mice received Pseudomonas aeruginosa injection in the back at 8h after burn injury. The animals were sacrificed at 24h after burn and lung tissues were harvested and examined for determining myeloperoxidase (MPO) activity, pulmonary microvascular dysfunction, NF-κB DNA binding activity, and IL-1β expression. Also, the lung and blood were harvested for bacterial count assay.
Thermal injury alone induced NF-κB DNA binding activity and neutrophil infiltration in the lung in WT but not in Tnfrsf1a(-/-) mice. A 50% total body surface area (TBSA) burn induced a significant increase of mortality in WT compared with Tnfrsf1a(-/-) mice. In contrast, P. aeruginosa injection with a 30% TBSA burn pretreatment enhanced IL-1β expression, bacterial counts in lung and blood, pulmonary microvascular dysfunction, and mortality in Tnfrsf1a(-/-) mice compared with WT mice. Injection of the IL-1 receptor antagonist, Anakinra, reduced P. aeruginosa infection with burn pretreatment-induced blood bacterial counts, IL-1β levels as well as permeability of lung, and mortality in Tnfrsf1a(-/-) mice.
Our findings suggest that thermal injury induces lung NF-κB activation and neutrophil sequestration through TNFα signaling. However, blocking TNF-α enhances P. aeruginosa infection-induced lung damage in burn mice via induction of IL-1β. Using an IL-1 receptor antagonist combined with the neutralization of TNF-α could be a useful strategy for decreasing P. aeruginosa infection-induced mortality in burn patients.
肿瘤坏死因子（TNFα）是一种促炎细胞因子，已成为人类脓毒症干预的靶点。然而，在感染性休克患者中，高剂量 TNF 受体融合蛋白抑制 TNF-α会导致患者生存率恶化。本研究旨在通过诱导白细胞介素-1β（IL-1β），研究阻断 TNF-α是否会增加感染性烧伤小鼠的死亡率。
WT 或 Tnfrsf1a（-/-）小鼠在烧伤后 8 小时背部注射铜绿假单胞菌。烧伤后 24 小时处死动物，采集肺组织，检测髓过氧化物酶（MPO）活性、肺微血管功能障碍、NF-κB DNA 结合活性和 IL-1β表达。同时，采集肺和血液进行细菌计数检测。
单独的热损伤可诱导 WT 但不诱导 Tnfrsf1a（-/-）小鼠肺部 NF-κB DNA 结合活性和中性粒细胞浸润。50%全身表面积（TBSA）烧伤导致 WT 小鼠死亡率显著高于 Tnfrsf1a（-/-）小鼠。相反，与 WT 小鼠相比，用 30%TBSA 烧伤预处理后注射铜绿假单胞菌可增强 Tnfrsf1a（-/-）小鼠的 IL-1β表达、肺和血液中的细菌计数、肺微血管功能障碍和死亡率。与 Tnfrsf1a（-/-）小鼠相比，注射白细胞介素-1 受体拮抗剂阿那白滞素可降低烧伤预处理诱导的铜绿假单胞菌感染引起的血细菌计数、IL-1β水平以及肺通透性和死亡率。
我们的研究结果表明，热损伤通过 TNFα 信号诱导肺部 NF-κB 激活和中性粒细胞隔离。然而，阻断 TNF-α会通过诱导 IL-1β增强烧伤小鼠铜绿假单胞菌感染引起的肺损伤。使用白细胞介素-1 受体拮抗剂联合中和 TNF-α可能是降低烧伤患者铜绿假单胞菌感染引起的死亡率的有效策略。
