Liu J Y, Brass D M, Hoyle G W, Brody A R
Department of Pathology, Tulane University Medical Center, New Orleans, Louisiana 70112-2699, USA.
Am J Pathol. 1998 Dec;153(6):1839-47. doi: 10.1016/s0002-9440(10)65698-2.
We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alphaRKO) fail to develop fibroproliferative lesions after asbestos exposure. There is good evidence that TNF-alpha plays a major role in mediating interstitial pulmonary fibrosis. Our findings support this view and we present here new data obtained by in situ hybridization showing that expression of the genes coding for transforming growth factor alpha (TGF-alpha) and platelet-derived growth factor A-chain (PDGF-A) is reduced in the TNF-alphaRKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-alphaRKO mice show no increases over unexposed control animals. In contrast, wild-type control mice exposed to asbestos exhibit 15- to 20-fold increases in BrdU uptake and consequently develop fibrogenic lesions. Even though the levels of TNF-alpha gene expression and protein production were increased in the asbestos-exposed TNF-alphaRKO mice, the lack of receptor signaling protected the mice from developing fibroproliferative lesions. We agree with the view that TNF-alpha is essential for the development of interstitial pulmonary fibrosis and postulate that TNF-alpha mediates its effects through activation of other growth factors such as PDGF and TGF-alpha that control cell growth and matrix production.
我们已经证明，55kd和75kd的肿瘤坏死因子α（TNF-α）受体基因均敲除的C57BL/6-129杂交小鼠（TNF-αRKO）在接触石棉后不会发生纤维增生性病变。有充分证据表明，TNF-α在介导间质性肺纤维化中起主要作用。我们的研究结果支持这一观点，并且在此展示通过原位杂交获得的新数据，这些数据表明与对照动物相比，TNF-αRKO小鼠中编码转化生长因子α（TGF-α）和血小板衍生生长因子A链（PDGF-A）的基因表达降低。与此观察结果一致，TNF-αRKO小鼠肺中溴脱氧尿苷（BrdU）掺入的数据显示，与未接触的对照动物相比没有增加。相反，接触石棉的野生型对照小鼠的BrdU摄取增加了15至20倍，因此发生了纤维化病变。尽管在接触石棉的TNF-αRKO小鼠中TNF-α基因表达水平和蛋白质产生增加，但缺乏受体信号传导保护小鼠不发生纤维增生性病变。我们同意TNF-α对间质性肺纤维化的发展至关重要的观点，并推测TNF-α通过激活其他控制细胞生长和基质产生的生长因子（如PDGF和TGF-α）来介导其作用。
