Antao-Menezes Aurita, Turpin Elizabeth A, Bost Phillip C, Ryman-Rasmussen Jessica P, Bonner James C
Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
J Immunol. 2008 Mar 15;180(6):4200-7. doi: 10.4049/jimmunol.180.6.4200.
The inhalation of vanadium pentoxide (V(2)O(5)) results in bronchitis and airway fibrosis. The lung fibrotic response to V(2)O(5) partially resolves where fibroblasts first proliferate and deposit collagen, but then undergo growth arrest and apoptosis. STAT-1 mediates fibroblast growth arrest and apoptosis. We previously reported that STAT-1 is a protective factor and mice lacking STAT-1 are more susceptible to lung fibrosis. We also reported that V(2)O(5)-induced STAT-1 phosphorylation in lung fibroblasts requires H(2)O(2) and de novo protein synthesis. In this study, we identified IFN-beta as the protein that mediates STAT-1 activation by V(2)O(5) in normal human lung fibroblasts and identified NADPH and xanthine oxidase systems as sources of H(2)O(2) that drive IFN-beta gene expression. STAT-1 phosphorylation was decreased with neutralizing Abs to IFN-beta as well as an inhibitor of JAK. V(2)O(5) also increased transcription of an IFN-inducible and STAT-1-dependent chemokine, CXCL10. Inhibition of H(2)O(2)-generating enzyme systems NADPH oxidase by apocynin and xanthine oxidase by allopurinol individually reduced STAT-1 phosphorylation. Apocynin and allopurinol also decreased V(2)O(5)-induced IFN-beta mRNA levels and CXCL10 expression. IFN-alpha transcription was inhibited only by allopurinol. Taken together, these data indicate that fibroblasts play a role in the innate immune response to vanadium-induced oxidative stress by synthesizing IFN-beta and activating STAT-1 to cause growth arrest and increase levels of CXCL10, a potent antifibrotic factor. This mechanism is postulated to counterbalance profibrogenic mechanisms that follow V(2)O(5) injury.
吸入五氧化二钒（V₂O₅）会导致支气管炎和气道纤维化。肺对V₂O₅的纤维化反应在一定程度上得到缓解，在此过程中，成纤维细胞首先增殖并沉积胶原蛋白，但随后会经历生长停滞和凋亡。信号转导和转录激活因子1（STAT-1）介导成纤维细胞的生长停滞和凋亡。我们之前报道过，STAT-1是一种保护因子，缺乏STAT-1的小鼠更容易患肺纤维化。我们还报道过，V₂O₅诱导的肺成纤维细胞中STAT-1磷酸化需要过氧化氢（H₂O₂）和从头合成蛋白质。在本研究中，我们确定干扰素-β（IFN-β）是在正常人肺成纤维细胞中介导V₂O₅激活STAT-1的蛋白质，并确定烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和黄嘌呤氧化酶系统是驱动IFN-β基因表达的H₂O₂来源。用抗IFN-β的中和抗体以及一种Janus激酶（JAK）抑制剂可降低STAT-1磷酸化。V₂O₅还增加了一种IFN诱导且依赖STAT-1的趋化因子CXCL10的转录。阿朴吗啡抑制产生H₂O₂的酶系统烟酰胺腺嘌呤二核苷酸磷酸氧化酶，别嘌呤醇抑制黄嘌呤氧化酶，分别降低了STAT-1磷酸化。阿朴吗啡和别嘌呤醇还降低了V₂O₅诱导的IFN-β mRNA水平和CXCL10表达。只有别嘌呤醇抑制了干扰素-α（IFN-α）转录。综上所述，这些数据表明成纤维细胞通过合成IFN-β和激活STAT-1以导致生长停滞并增加强效抗纤维化因子CXCL10的水平，从而在对钒诱导的氧化应激的固有免疫反应中发挥作用。推测该机制可平衡V₂O₅损伤后的促纤维化机制。
