Keane M P, Belperio J A, Moore T A, Moore B B, Arenberg D A, Smith R E, Burdick M D, Kunkel S L, Strieter R M
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
J Immunol. 1999 May 1;162(9):5511-8.
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.
很少有研究探讨博来霉素诱导的肺纤维化发展过程中肺血管重塑的重要性。为了发生纤维增生和细胞外基质沉积，新生血管形成必须有几何级的增加。我们推测，在博来霉素诱导的肺纤维化过程中，纤维增生发病机制中的净血管生成和细胞外基质沉积部分依赖于促血管生成的CXC趋化因子巨噬细胞炎性蛋白-2（MIP-2）的过表达。为了验证这一假设，我们通过特异性酶联免疫吸附测定法（ELISA）测量了博来霉素处理的或对照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，与盐水处理的对照组相比，博来霉素处理的小鼠肺组织中MIP-2的含量显著增加，这与更强的血管生成反应和全肺羟脯氨酸含量相关。使用体内血管生成生物测定法，中和抗MIP-2抗体抑制了第16天博来霉素处理的肺标本的血管生成活性。此外，当通过被动免疫在体内耗尽MIP-2时，博来霉素诱导的肺纤维化显著减轻，而肺中性粒细胞的存在、成纤维细胞增殖或胶原基因表达没有变化。这也伴随着血管生成的减少。这些结果表明，促血管生成的CXC趋化因子MIP-2是调节肺纤维化中血管生成/纤维化的重要因素。
