Anti-TNF-alpha therapy does not ameliorate disease in a model of acute virus-endotoxin mediated respiratory disease in pigs.
Anti-TNF-alpha therapy does not ameliorate disease in a model of acute virus-endotoxin mediated respiratory disease in pigs.
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DOI：
10.1016/j.vetimm.2010.04.003
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发表时间：
2010-09-15
影响因子：
1.8
通讯作者：
Van Reeth K
中科院分区：
文献类型：
--
作者：
Atanasova K;Van Gucht S;Van Reeth K
肿瘤坏死因子-α（TNF-α）已被证明在许多炎症性疾病中发挥作用。目前，抗TNF-α药物（例如依那西普）用于治疗人类自身免疫性疾病。本研究旨在阐明TNF-α在病毒-内毒素诱导的呼吸道疾病发展中的作用。使用22头剖腹产的初乳剥夺猪。最初，在4头猪中评估了依那西普单独给药0.5 mg/每种途径/每头猪的肺内和腹膜内给药后，在肺和循环中的可用性以及可能的临床和炎症效应。在所有动物的支气管肺泡灌洗液（BAL）、腹腔灌洗液和血清中检测到高抗TNF-α活性，至少在接种后8 h（HPI）。无临床症状、肺部病变、肺细胞浸润及BAL中IFN-α、IL-1、IL-6、IL-12和TNF-α的诱导。随后，在8头猪中评估了依那西普阻断猪TNF-α的能力及其对上述参数和肺病毒滴度的影响。24 h后分别用猪呼吸道冠状病毒（PRCV）和脂多糖（LPS）进行肠道内接种。在LPS接种时，通过与初始实验相同的途径和剂量给予依那西普。将这些参数与仅接受PRCV-LPS的对照组（n = 8）进行比较。在LPS接种后4小时处死每组一半动物，其余动物在8小时处死。在4 HPI安乐死的4只动物中，有3只动物的TNF-α被完全中和，并且在所有时间均显著低于PRCV-LPS组。两组患者在疾病严重程度、肺部病变、病毒复制、肺细胞浸润或IFN-α、IL-1、IL-6和IL-12/IL-23水平方面均无显著差异。在PRCV-LPS呼吸系统疾病模型中，单独阻断TNF-α不足以改善疾病，这可能是由于促炎细胞因子级联反应的冗余，或其他未鉴定的疾病介质的参与。
Tumour necrosis factor-α (TNF-α) has been shown to play a role in many inflammatory conditions. Currently anti-TNF-α drugs (e.g. etanercept) are used in humans for treatment of autoimmune diseases. In this study we aimed to elucidate the role of TNF-α in the development of virus-endotoxin-induced respiratory disease. Twenty-two caesarean derived colostrum deprived pigs were used. Initially, the availability in the lungs and circulation, and possible clinical and inflammatory effects of etanercept alone were assessed in 4 pigs after intratracheal and intraperitoneal administration of 0.5 mg/per route/per pig. High anti-TNF-α activity was detected in bronchoalveolar lavage (BAL) fluids, peritoneal lavage fluids and serum of all animals for at least 8 h post-inoculation (HPI). No clinical symptoms, lung lesions, lung cell infiltration or induction of IFN-α, IL-1, IL-6, IL-12 and TNF-α in BAL were detected. Subsequently, the ability of etanercept to block porcine TNF-α and its effect on the above mentioned parameters and on lung virus titres were assessed in 8 pigs. They were inoculated intratracheally with porcine respiratory coronavirus (PRCV) followed by lipopolysaccharide (LPS) 24 h later. Etanercept was administered at the time of LPS inoculation via the same routes and dose as in the initial experiment. The parameters were compared with a control group (n = 8), receiving only PRCV-LPS. Half of the animals from each group were euthanized at 4 and the rest at 8 h after LPS inoculation. TNF-α was completely neutralized in 3 of the 4 animals euthanized at 4 HPI and significantly lower than in the PRCV-LPS group at all times. No significant differences in disease severity, lung lesions, virus replication, lung cell infiltration or levels of IFN-α, IL-1, IL-6 and IL-12/IL-23 were observed between the two groups. Blocking of TNF-α alone was not sufficient to ameliorate disease in the PRCV-LPS model of respiratory disease, possibly due to the redundancy in the proinflammatory cytokine cascade, or the involvement of other unidentified disease mediators.
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