Zhang K, Gharaee-Kermani M, McGarry B, Remick D, Phan S H
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA.
J Immunol. 1997 Jan 15;158(2):954-9.
Despite abundant evidence documenting the importance of TNF-alpha in the pathogenesis of pulmonary fibrosis, its actual role has not been fully elucidated. Recent observations also indicate that eosinophils found in fibrotic lung express elevated levels of cytokines known to be important in lung fibrosis. These findings suggest a possible role for TNF-alpha in eosinophil recruitment and cytokine expression in this disease. To examine this hypothesis, pulmonary fibrosis was induced in mice by endotracheal bleomycin treatment, and separate groups of animals were also treated with either anti-TNF-alpha Ab or control serum. On days 7 and 14 post-bleomycin treatment, lungs were harvested and analyzed for fibrosis, cytokine expression, and eosinophil influx. Anti-TNF-alpha caused a significant reduction in lung fibrosis, as indicated by a reduction in hydroxyproline content, which was accompanied by suppression of lung TGF-beta1, IL-5, and JE mRNA expression. Examination of tissue sections revealed a significant reduction in lung eosinophils and overall cellularity by anti-TNF-alpha treatment without a significant effect on the number of lung macrophages. The number of IL-5-expressing cells was also significantly reduced by anti-TNF-alpha treatment. Since IL-5 is important in eosinophil differentiation, activation, and recruitment, these findings suggest a novel mechanism by which TNF-alpha could mediate pulmonary fibrosis via induction of IL-5-mediated eosinophil recruitment and fibrogenic cytokine production. Since these eosinophil-derived cytokines include JE/monocyte chemotactic factor-1 and TGF-beta1, this cytokine networking orchestrated by TNF-alpha could, in turn, amplify the inflammatory response and drive the progression to fibrosis and end-stage lung disease.
尽管有大量证据证明肿瘤坏死因子-α（TNF-α）在肺纤维化发病机制中具有重要作用，但其实际作用尚未完全阐明。最近的观察结果还表明，在纤维化肺组织中发现的嗜酸性粒细胞表达的细胞因子水平升高，而这些细胞因子在肺纤维化中已知具有重要作用。这些发现提示TNF-α在该疾病的嗜酸性粒细胞募集和细胞因子表达中可能发挥作用。为了验证这一假设，通过气管内注射博来霉素诱导小鼠发生肺纤维化，并且将单独的动物组分别用抗TNF-α抗体或对照血清进行处理。在博来霉素处理后的第7天和第14天，采集肺组织并分析纤维化、细胞因子表达和嗜酸性粒细胞浸润情况。抗TNF-α导致肺纤维化显著减轻，这表现为羟脯氨酸含量降低，同时伴有肺组织中转化生长因子-β1（TGF-β1）、白细胞介素-5（IL-5）和JE mRNA表达受到抑制。组织切片检查显示，抗TNF-α处理使肺组织中的嗜酸性粒细胞和总体细胞数量显著减少，而对肺巨噬细胞数量没有显著影响。抗TNF-α处理还使表达IL-5的细胞数量显著减少。由于IL-5在嗜酸性粒细胞的分化、激活和募集中具有重要作用，这些发现提示了一种新的机制，即TNF-α可能通过诱导IL-5介导的嗜酸性粒细胞募集和促纤维化细胞因子产生来介导肺纤维化。由于这些嗜酸性粒细胞衍生的细胞因子包括JE/单核细胞趋化因子-1和TGF-β1，由TNF-α精心编排的这种细胞因子网络反过来可能会放大炎症反应，并推动疾病进展为纤维化和终末期肺病。
