MOLECULAR MECHANISMS OF ANTIFIBROTIC EFFECT OF INTERFERON-GAMMA IN BLEOMYCIN MOUSE MODEL OF LUNG FIBROSIS - DOWN-REGULATION OF TGF-BETA AND PROCOLLAGEN-I AND PROCOLLAGEN-III GENE-EXPRESSION
MOLECULAR MECHANISMS OF ANTIFIBROTIC EFFECT OF INTERFERON-GAMMA IN BLEOMYCIN MOUSE MODEL OF LUNG FIBROSIS - DOWN-REGULATION OF TGF-BETA AND PROCOLLAGEN-I AND PROCOLLAGEN-III GENE-EXPRESSION
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DOI：
10.3109/01902149509050842
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发表时间：
1995-09-01
影响因子：
1.7
通讯作者：
GIRI, SN
中科院分区：
文献类型：
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作者：
GURUJEYALAKSHMI, G;GIRI, SN
本研究旨在阐明干扰素γ（IFN-γ）在博莱霉素（BL）-小鼠肺纤维化模型中的抗纤维化作用的机制。通过北方和狭缝印迹分析，在有和没有IFN-γ治疗的BL-小鼠肺纤维化模型中研究转化生长因子（TGF-β）和前胶原I和III及其mRNA的表达。对通过肌肉内途径接受生理盐水或BL、通过肌肉内途径接受和不接受IFN-γ治疗的小鼠肺中前胶原和TGF-β mRNA含量的时间变化进行定量。TGF-β mRNA水平迅速增加，在第5天达到峰值，而前胶原α（1）（I）和α（1）（III）mRNA水平在BL滴注后10天达到峰值。BL处理动物中这些mRNA的峰值水平比对照动物高5 - 7倍。BL处理小鼠肺中TGF-β mRNA的增加先于I型和III型前胶原mRNA合成的增加。与相应的生理盐水对照组相比，BL处理还显著增加了3至14天的羟脯氨酸含量。在滴注后10天，生理盐水对照组中的223 μ g/肺最大增加至447 μ g/肺。每天用IFN-γ治疗显著降低了BL诱导的TGF-β和前胶原α（1）（I）和α（1）（III）mRNA水平的增加，而对肺β-肌动蛋白mRNA水平没有任何影响。IFN-γ处理还导致BL诱导的肺羟脯氨酸含量增加显著降低，在7天时从417 μ g/肺降低至283 μ g/肺，在10天时从447 μ g/肺降低至264 μ g/肺。从本研究的发现可以得出结论，IFN-γ在BL-小鼠肺纤维化模型中的抗纤维化作用的细胞机制是最初下调BL-诱导的TGF-β mRNA的过表达，随后下调前胶原mRNA，导致胶原含量降低。
The present study was undertaken to elucidate the mechanism for the antifibrotic effect of interferon gamma (IFN-gamma) in the bleomycin (BL)-mouse model of lung fibrosis. The expression of transforming growth factor (TGF-beta) and procollagen I and III and their mRNAs was investigated in the BL-mouse model of lung fibrosis with and without IFN-gamma treatment by Northern and slot blot analyses. Temporal changes in the content of procollagen and TGF-beta mRNAs in the lungs of mice receiving saline or BL by intratracheal route, with and without IFN-gamma treatment by intramuscular route, were quantitated. The level of TGF-beta mRNA increased rapidly and peaked at day 5, whereas the levels of mRNAs for procollagens alpha(1)(I) and alpha(1)(III) peaked at IO days after BL instillation The peak levels of these mRNAs in BL-treated animals were five- to sevenfold higher than those of the control. The increase in TGF-beta mRNA in the lungs of BL-treated mice preceded the increase in the synthesis of type I and type III procollagen mRNAs. BL treatment also increased the hydroxyproline content significantly from 3 to 14 days as compared to the corresponding saline control groups. A maximal increase to 447 mu g/lung from 223 mu g/lung in saline control was obtained at 10 days after instillation. Daily treatment with IFN-gamma markedly reduced the BL-induced increases in the mRNA levels of TGF-beta, and procollagen alpha(1)(I) and alpha(1)(III) without any effect on the lung level of beta-actin mRNA. IFN-gamma treatment also caused significant reduction in the BL-induced increase in the lung hydroxyproline content from 417 to 283 mu g/lung at 7 days and from 447 to 264 mu g/lung at 10 days. It may be concluded from the findings of the present study that the cellular mechanisms for the antifibrotic effect of IFN-gamma in the BL-mouse model of lung fibrosis are to initially downregulate the BL-induced overexpression of TGF-beta mRNA, and subsequently procollagen mRNAs, leading to a decreased collagen content.