Shanley T P, Schmal H, Friedl H P, Jones M L, Ward P A
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
J Immunol. 1995 May 1;154(9):4793-802.
The role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the pathogenesis of acute lung injury in rats after intrapulmonary deposition of IgG immune complexes or intratracheal administration of LPS has been assessed. Critical to these studies was the cloning and functional expression of rat MIP-1 alpha. The resulting product shared 92% and 90% homology with the known murine sequence at the cDNA level and protein level, respectively. Recombinant rat MIP-1 alpha exhibited dose-dependent chemotactic activity for both rat and human monocytes and neutrophils, which could be blocked by anti-murine MIP-1 alpha Ab. Rat MIP-1 alpha mRNA and protein expression were determined as a function of time in both injury models. A time-dependent increase in MIP-1 alpha mRNA in lung extracts was observed in both models. In the LPS model, MIP-1 alpha protein could also be detected in bronchoalveolar lavage (BAL) fluids by Western blot analysis. Anti-MIP-1 alpha administered at commencement of IgG immune complex- or LPS-induced injury resulted in significant reductions in BAL neutrophils as well as in injury as measured by pulmonary vascular permeability. Under such conditions, in both models TNF-alpha content in BAL fluids was substantially reduced as compared with BAL fluids from positive control animals. These findings suggest that rat MIP-1 alpha plays an important role in the development of lung injury in these neutrophil-dependent models. The role of MIP-1 alpha seems to be related to production of TNF-alpha, which in turn up-regulates vascular adhesion molecules required for neutrophil influx.
已经评估了巨噬细胞炎性蛋白-1α（MIP-1α）在大鼠经肺内注射IgG免疫复合物或气管内给予脂多糖（LPS）后急性肺损伤发病机制中的作用。这些研究的关键在于大鼠MIP-1α的克隆和功能表达。所得产物在cDNA水平和蛋白质水平上分别与已知的小鼠序列具有92%和90%的同源性。重组大鼠MIP-1α对大鼠和人类单核细胞及中性粒细胞均表现出剂量依赖性趋化活性，这一活性可被抗小鼠MIP-1α抗体阻断。在两种损伤模型中，均测定了大鼠MIP-1α mRNA和蛋白质表达随时间的变化情况。在两种模型中均观察到肺提取物中MIP-1α mRNA随时间增加。在LPS模型中，通过蛋白质印迹分析还可在支气管肺泡灌洗（BAL）液中检测到MIP-1α蛋白。在IgG免疫复合物或LPS诱导损伤开始时给予抗MIP-1α，可使BAL中性粒细胞显著减少，同时肺血管通透性所测量的损伤也显著减轻。在这种情况下，与阳性对照动物的BAL液相比，两种模型中BAL液中的肿瘤坏死因子-α（TNF-α）含量均大幅降低。这些发现表明，大鼠MIP-1α在这些中性粒细胞依赖性模型的肺损伤发展中起重要作用。MIP-1α的作用似乎与TNF-α的产生有关，而TNF-α又上调中性粒细胞流入所需的血管黏附分子。
