Zhang K, Phan S H
Department of Pathology, University of Michigan, Ann Arbor, USA.
Biol Signals. 1996 Jul-Aug;5(4):232-9. doi: 10.1159/000109195.
In the past several years, significant progress in many aspects of pulmonary fibrosis research has been made. Among them, the finding that a variety of cytokines play important roles in the complex process appears most intriguing. These cytokines include at least transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha), platelet-derived growth factor, fibroblast growth factors, (TGF-alpha), interleukin-1, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1 alpha. These cytokines have been demonstrated to be produced at the sites of active fibrosis where they appear to be expressed by activated inflammatory cells, such as macrophages and eosinophils. More interestingly, other noninflammatory lung cells including mesenchymal cells, such as myofibroblasts, and epithelial cells, have been found to be significant sources as well, albeit in most instances at somewhat different time points than those by inflammatory cells. Study of the individual cytokines in vitro has revealed a variety of potential roles for these cytokines in the regulation of the fibrotic process in vivo, including chemoattractant, mitogenic activities for fibroblasts, stimulation of extracellular matrix and alpha-smooth muscle actin gene expression, alteration of the contractile phenotype of fibroblasts and regulation of diverse functions of lung inflammatory and epithelial cells which can further impact on the fibrotic process by autocrine and paracrine mechanisms. Of these cytokines, it appears that TGF-beta is probably the most important cytokine in terms of the direct stimulation of lung matrix expression which typifies fibrosis. Recently however, there is accumulating evidence to indicate that the situation is much more complex than any one single cytokine being solely responsible for the fibrotic response. The concept of complex lung cytokine networks, orchestrated by a few key cytokines, such as TNF-alpha, being responsible for this response has received strong support from recent studies. This means that it is the balance of positive (profibrogenic) and negative (antifibrogenic) forces generated from interaction among the various cytokines constituting these networks, which may finally determine the outcome of lung injury and inflammation. The importance of these cytokines also suggests new potential targets for designing new therapies for progressive pulmonary fibrosis, and perhaps their utility in prognostication as well.
在过去几年中，肺纤维化研究的许多方面都取得了重大进展。其中，发现多种细胞因子在这一复杂过程中发挥重要作用显得最为引人关注。这些细胞因子至少包括转化生长因子-β（TGF-β）、肿瘤坏死因子-α（TNF-α）、血小板衍生生长因子、成纤维细胞生长因子、（TGF-α）、白细胞介素-1、单核细胞趋化蛋白-1和巨噬细胞炎性蛋白-1α。这些细胞因子已被证明在活动性纤维化部位产生，它们似乎由活化的炎性细胞如巨噬细胞和嗜酸性粒细胞表达。更有趣的是，其他非炎性肺细胞，包括间充质细胞如肌成纤维细胞和上皮细胞，也被发现是重要来源尽管在大多数情况下，它们产生细胞因子的时间点与炎性细胞有所不同。对单个细胞因子的体外研究揭示了这些细胞因子在体内纤维化过程调节中的多种潜在作用，包括对成纤维细胞的趋化作用、促有丝分裂活性、刺激细胞外基质和α-平滑肌肌动蛋白基因表达、改变成纤维细胞的收缩表型以及调节肺炎性细胞和上皮细胞的多种功能，这些细胞可通过自分泌和旁分泌机制进一步影响纤维化过程。在这些细胞因子中，就直接刺激典型纤维化的肺基质表达而言，TGF-β可能是最重要的细胞因子。然而最近，越来越多的证据表明情况比任何一种单一细胞因子单独导致纤维化反应要复杂得多。由一些关键细胞因子如TNF-α精心编排的复杂肺细胞因子网络负责这种反应的概念得到了最近研究的有力支持。这意味着，由构成这些网络的各种细胞因子之间相互作用产生的正（促纤维化）负（抗纤维化）力量的平衡，最终可能决定肺损伤和炎症的结果。这些细胞因子的重要性还提示了为进行性肺纤维化设计新疗法的新潜在靶点，或许它们在预后评估中也有用处。
