Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.
Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.
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DOI：
10.4049/jimmunol.162.9.5511
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发表时间：
1999-05
影响因子：
4.4
通讯作者：
M. Keane;J. Belperio;T. Moore;B. Moore;D. Arenberg;Robert E. Smith;M. Burdick;S. Kunkel;R. Strieter
中科院分区：
文献类型：
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作者：
M. Keane;J. Belperio;T. Moore;B. Moore;D. Arenberg;Robert E. Smith;M. Burdick;S. Kunkel;R. Strieter
很少有研究探讨博莱霉素诱导的肺纤维化发展过程中肺部血管重塑的重要性。为了发生纤维增生和细胞外基质沉积，新血管形成必须呈几何级数增加。我们假设，纤维增生发病过程中的净血管生成和博来霉素诱导的肺纤维化过程中细胞外基质的沉积部分依赖于血管生成CXC趋化因子巨噬细胞炎症蛋白2（MIP-2）的过度表达。为了检验这一假设，我们通过特异性 ELISA 测量了博莱霉素处理或对照 CBA/J 小鼠全肺匀浆中的 MIP-2，并将这些水平与肺羟脯氨酸相关联。我们发现，与用盐水处理的对照小鼠的肺组织相比，用博来霉素处理的小鼠的肺组织中 MIP-2 的存在显着增加，这与更大的血管生成反应和肺总羟脯氨酸含量相关。使用体内血管生成生物测定，中和抗 MIP-2 Abs 抑制第 16 天博来霉素处理的肺样本的血管生成活性。此外，当通过被动免疫在体内消耗MIP-2时，博莱霉素诱导的肺纤维化显着减少，而肺中性粒细胞的存在、成纤维细胞增殖或胶原蛋白基因表达没有变化。与此同时，血管生成也减少。这些结果表明，血管生成CXC趋化因子MIP-2是调节肺纤维化中血管生成/纤维化的重要因子。
Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis. For fibroplasia and deposition of extracellular matrix to occur, there must be a geometric increase in neovascularization. We hypothesized that net angiogenesis during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis are dependent in part upon an overexpression of the angiogenic CXC chemokine, macrophage inflammatory protein-2 (MIP-2). To test this hypothesis, we measured MIP-2 by specific ELISA in whole lung homogenates in either bleomycin-treated or control CBA/J mice and correlated these levels with lung hydroxyproline. We found that lung tissue from mice treated with bleomycin, compared with that from saline-treated controls, demonstrated a significant increase in the presence of MIP-2 that was correlated to a greater angiogenic response and total lung hydroxyproline content. Neutralizing anti-MIP-2 Abs inhibited the angiogenic activity of day 16 bleomycin-treated lung specimens using an in vivo angiogenesis bioassay. Furthermore, when MIP-2 was depleted in vivo by passive immunization, bleomycin-induced pulmonary fibrosis was significantly reduced without a change in the presence of pulmonary neutrophils, fibroblast proliferation, or collagen gene expression. This was also paralleled by a reduction in angiogenesis. These results demonstrate that the angiogenic CXC chemokine, MIP-2, is an important factor that regulates angiogenesis/fibrosis in pulmonary fibrosis.