Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice.
Titration of non-replicating adenovirus as a vector for transducing active TGF-beta1 gene expression causing inflammation and fibrogenesis in the lungs of C57BL/6 mice.
复制标题
非复制腺病毒作为转导活性 TGF-β1 基因表达的载体的滴定，导致 C57BL/6 小鼠肺部炎症和纤维化。
DOI：
10.1046/j.1365-2613.2002.00229.x
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发表时间：
2002
影响因子：
3
通讯作者：
Brody,ArnoldR
中科院分区：
文献类型：
--
作者：
Warshamana,GSakuntala;Pociask,DerekA;Fisher,KrishnaJ;Liu,Jing-Yao;Sime,PatriciaJ;Brody,ArnoldR
Investigators have shown that interstitial pulmonary fibrosis (IPF) can be induced in rats by overexpressing transforming growth factor beta1(TGF‐β1) through a replication‐deficient recombinant adenovirus vector instilled into the lungs (Simeet al. 1997). We have shown that this vector induces IPF in fibrogenic‐resistant tumour necrosis factor alpha‐receptor knockout (TNF‐αRKO) mice (Liuet al. 2001). The object of our studies is to understand how peptide growth factors, such as TGF‐β1, mediate interstitial lung disease (ILD). To do so, we must be able to manipulate the dose of the factor and sort out its effects on multiple other mediators in the lung parenchyma. As a step in this complex process, in the studies reported here, we have determined the concentrations of the recombinant adenovirus vector carrying the gene for porcine active TGF‐β1(AVTGFβ1) that have little apparent effect, cause clear induction of disease, or severe disease. The disease largely resolves by 28 days in all cases, thus providing a valuable model to understand the mechanisms of the IPF that is mediated, at least in part, by TGF‐β1. The findings here show that 106plaque‐forming units (pfu) of AVTGFβ1, provide essentially a ‘no‐effect’ dose, but even this amount of TGF‐β1causes a significant increase in whole‐lung collagen by day 28 after treatment. In contrast, 108and 109pfu cause severe IPF in 4 days, whereas 107and 5 × 107are intermediate for all parameters studied, i.e. TGF‐β protein, inflammatory cells, cell proliferation, pro‐α 1(I) collagen gene expression and whole‐lung collagen accumulation, and expression of growth factors such as TGF‐β1, TNF‐α and PDGF‐A and ‐B. Interestingly enough, TGF‐β1, as a potent blocker of epithelial cell proliferation, appears to suppress airway epithelial cell growth that would be expected during the inflammatory phase of IPF. Thus, this model system helps us to understand some quantitative aspects of TGF‐β1biological activity and allows us to manipulate this potent factor as a mediator of interstitial fibrogenesis.
