TNF-α receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers
TNF-α receptor knockout mice are protected from the fibroproliferative effects of inhaled asbestos fibers
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DOI：
10.1016/s0002-9440(10)65698-2
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发表时间：
1998-12-01
影响因子：
6
通讯作者：
Brody, AR
中科院分区：
文献类型：
--
作者：
Liu, JY;Brass, DM;Brody, AR
我们已经证明，C57 BL/6-129杂交小鼠与基因的55 kd和75 kd受体的TNF-α敲除（TNF-α RKO）未能发展纤维增生性病变石棉暴露后。有充分的证据表明，TNF-α在介导肺间质纤维化中起主要作用。我们的研究结果支持这一观点，我们在这里提出了新的数据，通过原位杂交显示，表达的基因编码的转化生长因子α（TGF-α）和血小板衍生生长因子A链（PDGF-A）的TNF-α RKO小鼠与对照组相比，减少。根据这一观察结果，TNF-α RKO小鼠肺中溴脱氧尿苷（BrdU）掺入的数据显示，与未暴露的对照动物相比没有增加。相反，暴露于石棉野生型对照小鼠表现出BrdU摄取增加15- 20倍，并因此发展成纤维性病变。尽管暴露于石棉的TNF-alpha RKO小鼠中TNF-alpha基因表达和蛋白质产生水平增加，但受体信号传导的缺乏保护小鼠免于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，并假设TNF-α通过激活其他生长因子如PDGF和TGF-α介导其作用，这些生长因子控制细胞生长和基质产生。
We have demonstrated that C57BL/6-129 hybrid mice with genes for both the 55kd and 75kd receptors for TNF-alpha knocked out (TNF-alpha RKO) 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-alpha RKO mice compared with control animals. In accordance with this observation, data on bromodeoxyuridine (BrdU) incorporation in the lungs of the TNF-alpha RKO 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-alpha RKO 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.