Casale T B, Costa J J, Galli S J
Department of Internal Medicine, VA Medical Center, Iowa City, Iowa, USA.
Am J Respir Cell Mol Biol. 1996 Jul;15(1):35-44. doi: 10.1165/ajrcmb.15.1.8679220.
Tumor necrosis factor alpha (TNF alpha) is a potentially important cytokine in allergic respiratory reactions since it is released by mast cells and eosinophils, and it can promote mediator and cytokine release, adhesion molecule expression, and granulocyte migration. Therefore, we induced an IgE-mediated response in human lung samples and studied: (1) whether TNF alpha was produced in sufficient quantities to promote granulocyte migration; and (2) which cells expressed mRNA for TNF alpha using in situ hybridization. Lung fragments (from thoracotomy) were treated for 30 min with either anti-IgE, 1:100 dilution, or buffer (control). Anti-IgE treatment of 16 lungs resulted in greater than 4-fold increase in histamine release and the significant production of chemotactic activity. The chemotactic activity generated induced dose-responsive neutrophil and eosinophil migration through naked filters and endothelial and pulmonary epithelial monolayers. Fourteen of 16 samples had a significant increase in TNF alpha subsequent to anti-IgE treatment (P < 0.05). Anti-TNF alpha antibody (4 micrograms/ml) inhibited about 25% of the neutrophil chemotactic activity in supernatants from anti-IgE treated lungs. TNF alpha at a concentration measured after anti-IgE treatment of lung samples (50 pg/ml) induced neutrophil transendothelial migration. Finally, we found that anti-IgE treatment led to an increase in TNF alpha mRNA-positive cells by in situ hybridization (1.6/ mm2 experimental versus 0.5/mm2 control), some of which were eosinophils. Thus, human lung IgE-mediated responses in vitro results in: (1) release of TNF alpha in amounts sufficient to effect a biologic response, granulocyte chemotaxis: and (2) upregulation of mRNA for TNF alpha in eosinophils and other cells. These findings suggest that TNF alpha is an important effector molecule in the pathogenesis of allergic respiratory reactions.
肿瘤坏死因子α（TNFα）在过敏性呼吸道反应中可能是一种重要的细胞因子，因为它由肥大细胞和嗜酸性粒细胞释放，并且能够促进介质和细胞因子的释放、黏附分子的表达以及粒细胞的迁移。因此，我们在人肺样本中诱导了IgE介导的反应，并进行了如下研究：（1）TNFα的产生量是否足以促进粒细胞迁移；（2）利用原位杂交技术确定哪些细胞表达TNFα的mRNA。将（来自开胸手术的）肺组织碎片用抗IgE（1:100稀释）或缓冲液（对照）处理30分钟。对16个肺组织进行抗IgE处理后，组胺释放增加了4倍以上，并且产生了显著的趋化活性。所产生的趋化活性诱导了剂量依赖性的中性粒细胞和嗜酸性粒细胞通过裸滤膜以及内皮细胞和肺上皮单层的迁移。16个样本中有14个在抗IgE处理后TNFα显著增加（P < 0.05）。抗TNFα抗体（4微克/毫升）抑制了抗IgE处理的肺组织上清液中约25%的中性粒细胞趋化活性。肺样本经抗IgE处理后测得的TNFα浓度（50皮克/毫升）可诱导中性粒细胞跨内皮迁移。最后，我们通过原位杂交发现抗IgE处理导致TNFα mRNA阳性细胞增加（实验样本为1.6/平方毫米，对照样本为0.5/平方毫米），其中一些是嗜酸性粒细胞。因此，体外人肺IgE介导的反应导致：（1）释放足以产生生物学反应的TNFα量，即粒细胞趋化；（2）嗜酸性粒细胞和其他细胞中TNFα mRNA的上调。这些发现表明TNFα是过敏性呼吸道反应发病机制中的一个重要效应分子。
