Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice
Altered bleomycin-induced lung fibrosis in osteopontin-deficient mice
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DOI：
10.1152/ajplung.00394.2003
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发表时间：
2004-06-01
影响因子：
4.9
通讯作者：
O'Regan, AW
中科院分区：
文献类型：
--
作者：
Berman, JS;Serlin, D;O'Regan, AW
骨桥蛋白是一种多功能的基质细胞蛋白，在炎症和修复过程中大量表达。骨桥蛋白缺乏与异常的伤口修复有关，其特征是心脏和皮肤中异常的胶原纤维形成。最近的基因芯片研究发现，骨桥蛋白在人类和小鼠肺纤维化中大量表达。巨噬细胞和T细胞是骨桥蛋白的主要来源。然而，在肺纤维化过程中，当炎症消退时，骨桥蛋白表达继续增加，这表明在这种反应过程中骨桥蛋白的替代来源。在这项研究中，我们证明了骨桥蛋白的免疫反应，在肺上皮细胞和炎症细胞在人类普通间质性肺炎和小鼠博莱霉素诱导的肺纤维化。博莱霉素治疗后，骨桥蛋白基因敲除小鼠发生肺纤维化，其特征为远端空气间隙扩张，与野生型对照组相比I型胶原表达减少。在骨桥蛋白基因敲除小鼠中，活性转化生长因子-β（1）和基质金属蛋白酶-2的水平也显著降低。两组中III型胶原蛋白表达和总胶原酶活性相似。这些结果表明，骨桥蛋白的表达与重要的纤维化信号在肺和上皮细胞可能是一个重要的来源，骨桥蛋白在肺纤维化。
Osteopontin is a multifunctional matricellular protein abundantly expressed during inflammation and repair. Osteopontin deficiency is associated with abnormal wound repair characterized by aberrant collagen fibrillogenesis in the heart and skin. Recent gene microarray studies found that osteopontin is abundantly expressed in both human and mouse lung fibrosis. Macrophages and T cells are known to be major sources of osteopontin. During lung fibrosis, however, osteopontin expression continues to increase when inflammation has receded, suggesting alternative sources of ostepontin during this response. In this study, we demonstrate immunoreactivity for osteopontin in lung epithelial and inflammatory cells in human usual interstitial pneumonitis and murine bleomycin-induced lung fibrosis. After treatment with bleomycin, osteopontin-null mice develop lung fibrosis characterized by dilated distal air spaces and reduced type I collagen expression compared with wild-type controls. There is also a significant decrease in levels of active transforming growth factor-beta(1) and matrix metallo-proteinase-2 in osteopontin null mice. Type III collagen expression and total collagenase activity are similar in both groups. These results demonstrate that osteopontin expression is associated with important fibrogenic signals in the lung and that the epithelium may be an important source of osteopontin during lung fibrosis.