Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13 tissue inhibitor of metalloproteinase 1 expression in murine silicosis
Tumor necrosis factor receptor deficiency alters matrix metalloproteinase 13 tissue inhibitor of metalloproteinase 1 expression in murine silicosis
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DOI：
10.1164/ajrccm.163.1.2002123
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发表时间：
2001-01-01
影响因子：
24.7
通讯作者：
Selman, M
中科院分区：
文献类型：
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作者：
Ortiz, LA;Lasky, J;Selman, M
小鼠暴露于二氧化硅与增强的肿瘤坏死因子α（TNF-α）表达和基质沉积相关。TNF的调节通过转录因子的TNF受体（TNFR）活化介导。在目前的工作中，我们研究了个别TNFR在二氧化硅诱导的小鼠肺部炎症和基质沉积的重要性。我们研究了二氧化硅处理小鼠肺中TNF、α 1（I）胶原、间质胶原酶（MMP-13）及其抑制剂（TIMP-1）的RNA表达。此外，我们将MMP-13/TIMP-1 RNA丰度与C57 BL/6小鼠肺中转录因子AP-1和NF-κ B的活化以及两种类型TNFR（p55（-/-）或p75（-/-））之一缺陷的小鼠肺中的转录因子AP-1和NF-κ B的活化相关联，通过气管内滴注暴露于二氧化硅（0.2 g/kg）或盐水。暴露后28天处死动物，测定肺羟脯氨酸（HP）、TNF、α 1（I）胶原、MMP-13和TIMP-1 RNA丰度。AP-1和NF-κ B活化通过凝胶迁移试验进行研究。与C57 BL/6小鼠相比，p55（-/-）和p75（-/-）小鼠显著（*p < 0.05）降低了响应二氧化硅的肺HP积累。所有鼠株增强TNF和1（I）胶原mRNA响应二氧化硅。在所有鼠品系中也观察到响应二氧化硅的MMP-13 RNA表达增强（p < 0.05）。在C57 BL/6小鼠中观察到响应二氧化硅的TIMP-1 RNA表达增强（p < 0.05），但在p55（-/-）或p75（-/-）小鼠中未观察到。在所有鼠品系中观察到NF-κ B活化，而在二氧化硅处理后仅在C57 BL/6小鼠中观察到AP-1活化。这些数据表明TNFR缺失改变了MMP-13/TIMP-1的表达，有利于基质降解。
Murine exposure to silica is associated with enhanced tumor necrosis factor alpha (TNF-alpha) expression and matrix deposition. The regulation of TNF is mediated through TNF receptor (TNFR) activation of transcription factors. In the present work we have studied the importance of the individual TNFR in silica-induced lung inflammation and matrix deposition in mice. We studied RNA expression of TNF, alpha1(I) collagen, interstitial collagenase (MMP-13), and its inhibitor (TIMP-1) in the lungs of silica-treated mice. Furthermore, we correlated MMP-13/TIMP-1 RNA abundance with activation of the transcription factors AP-1 and NF-kappaB in the lungs of C57BL/6 mice, and of mice deficient in one of the two types of TNFR (p55(-/-) or p75(-/-)), exposed to silica (0.2 g/kg) or saline by intratracheal instillation. Animals were killed 28 d after exposure and lung hydroxyproline (HP), TNF, alpha1(I) collagen, MMP-13, and TIMP-1 RNA abundance was measured. AP-1 and NF-kappaB activation was studied by gel-shift assays. Compared with C57BL/6 mice, p55(-/-) and p75(-/-) mice significantly (*p < 0.05) decreased lung HP accumulation in response to silica. All murine strains enhanced TNF and 1(I) collagen mRNA in response to silica. Enhanced (p < 0.05) MMP-13 RNA expression was also observed in all murine strains in response to silica. Enhanced (p < 0.05) TIMP-1 RNA expression was observed in C57BL/6 mice, but not in p55(-/-) or p75(-/-) mice, in response to silica. NF-KB activation was observed in all murine strains, whereas AP-1 activation was observed only in C57BL/6 mice after silica treatment. These data suggest that TNFR deletion modifies MMP-13/TIMP-1 expression in favor of matrix degradation.