INCREASED EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA ISOFORMS (BETA(1), BETA(2), BETA(3)) IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS
INCREASED EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA ISOFORMS (BETA(1), BETA(2), BETA(3)) IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS
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DOI：
10.1165/ajrcmb.13.1.7541221
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发表时间：
1995-07-01
影响因子：
6.4
通讯作者：
MARSHALL, BC
中科院分区：
文献类型：
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作者：
SANTANA, A;SAXENA, B;MARSHALL, BC
有证据表明，转化生长因子β（TGF-β）可能通过诱导细胞外基质积累在各种纤维增生性疾病中发挥核心作用。三种哺乳动物TGF-β亚型存在于正常肺中，但对它们在肺损伤和修复过程中的表达知之甚少。为了更全面地了解TGF-β在肺修复中的作用，我们使用免疫组织化学和原位杂交技术研究了TGF-β（1）、TGF-β（2）和TGF-β亚型在博莱霉素诱导的肺纤维化模型中的表达。我们发现三种TGF-β亚型以相同的模式广泛分布于正常大鼠肺中：气道、血管、肺实质和肺泡巨噬细胞。在一般情况下，TGF-β mRNA和蛋白的分布相吻合，然而，支气管上皮细胞是一个显着的例外，表现出免疫反应性，但没有mRNA的表达。在博来霉素诱导的损伤的“炎症"阶段（第1天和第3天），损伤区域中所有三种TGF-β亚型的mRNA和蛋白表达增加，最显著的是在实质细胞和肺泡巨噬细胞中。在后期修复阶段（第7天和第14天），在纤维化发展区域中TGF-β亚型表达进一步增加，先前不表达TGF-β mRNA的支气管上皮显示出三种亚型mRNA的强烈表达，同时免疫反应性增加。这些发现暗示三种哺乳动物TGF-β亚型在导致肺纤维化的失调修复过程中。此外，支气管上皮TGF-β mRNA和蛋白表达的模式表明，在纤维化的“修复”阶段，在该部位可能发生从正常肺中的旁分泌作用模式到自分泌作用模式的转变。
Evidence suggests that transforming growth factor beta (TGF-beta) may play a central role in a variety of fibroproliferative disorders via the induction of extracellular matrix accumulation. The three mammalian TGF-beta isoforms are present in the normal lung, but very little is known about their expression during lung injury and repair. To more fully understand the role of TGF-beta in lung repair, we investigated the expression of the TGF-beta(1), TGF-beta(2), and TGF-beta, isoforms in a bleomycin-induced model of pulmonary fibrosis using immunohistochemical and in situ hybridization techniques. We found expression of the three TGF-beta isoforms, in an identical pattern, widely distributed throughout the normal rat lung: in airways, blood vessels, lung parenchyma, and alveolar macrophages. In general, the distribution of TGF-beta mRNA and protein coincided; however, bronchial epithelial cells were a notable exception, exhibiting immunoreactivity but no mRNA expression. During the ''inflammatory'' phase (days 1 and 3) of bleomycin-induced injury there was an increase in the mRNA and protein expression of all three TGF-beta isoforms in the injured areas, most prominently in parenchymal cells and alveolar macrophages. There was a further increase in TGF-beta isoform expression in the areas of developing fibrosis during the later reparative phase (days 7 and 14), and the bronchial epithelium, previously not expressing TGF-beta mRNA, showed strong expression of mRNA for the three isoforms concomitant with increased immunoreactivity. These findings implicate the three mammalian TGF-beta isoforms in the dysregulated repair process that results in pulmonary fibrosis. Furthermore, the pattern of TGF-beta mRNA and protein expression by the bronchial epithelium suggests that a transition may occur at this site from a paracrine mode of action in the normal lung to an autocrine mode of action during the ''reparative'' phase of fibrosis.