Kilgore K S, Imlay M M, Szaflarski J P, Silverstein F S, Malani A N, Evans V M, Warren J S
Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
Lab Invest. 1997 Feb;76(2):191-201.
Monocyte chemoattractant protein-1 (MCP-1), which is required for full development of glucan-induced granulomas, in the rat, is expressed in the walls of blood vessels at sites of glucan embolization. Early (1 hour) vessel wall expression of MCP-1 is temporally and anatomically linked to the transient accumulation of neutrophils, even though these cells are not present within definitive lesions. To ascertain the potential pathophysiologic role of neutrophils in glucan-induced granuloma formation, rats were neutrophil-depleted using specific antiserum. There was a marked reduction in mean granuloma size and number in neutrophil-depleted animals when compared with neutrophil-sufficient controls. To determine potential mechanisms through which neutrophils may participate in granuloma formation, the antioxidant enzymes superoxide dismutase and catalase were administered to neutrophil-sufficient animals that had received glucan. Superoxide dismutase treatment did not reduce granuloma formation, whereas catalase treatment resulted in decreased granuloma size, suggesting that H2O2 plays an important role in this process. The local expression of MCP-1 mRNA and protein, as determined by in situ hybridization and immunohistochemical analysis, respectively, was decreased in both neutrophil-depleted and catalase-treated animals but not in superoxide dismutase-treated rats. Quiescent human umbilical vein endothelial cells incubated with either H2O2 or activated neutrophils secreted MCP-1. These data indicate that neutrophils and H2O2 are required for both full granuloma development and early blood vessel wall-associated MCP-1 expression after glucan infusion. These in vivo data, coupled with in vitro data that indicate that both catalase-sensitive reagent H2O2 and neutrophil-derived reactive oxygen intermediates (ie, H2O2) can induce MCP-1 secretion by human umbilical vein endothelial cells, support the hypothesis that neutrophils and neutrophil-derived products (H2O2) influence granuloma formation through induction of local MCP-1 expression.
单核细胞趋化蛋白-1（MCP-1）在大鼠体内是葡聚糖诱导肉芽肿完全形成所必需的，它在葡聚糖栓塞部位的血管壁中表达。MCP-1在血管壁的早期（1小时）表达在时间和解剖学上与中性粒细胞的短暂积聚相关，尽管这些细胞并不存在于最终病变中。为了确定中性粒细胞在葡聚糖诱导的肉芽肿形成中的潜在病理生理作用，使用特异性抗血清使大鼠中性粒细胞减少。与中性粒细胞充足的对照组相比，中性粒细胞减少的动物中肉芽肿的平均大小和数量显著减少。为了确定中性粒细胞可能参与肉芽肿形成的潜在机制，将抗氧化酶超氧化物歧化酶和过氧化氢酶给予接受葡聚糖的中性粒细胞充足的动物。超氧化物歧化酶治疗并未减少肉芽肿的形成，而过氧化氢酶治疗导致肉芽肿大小减小，这表明H2O2在该过程中起重要作用。分别通过原位杂交和免疫组织化学分析确定，在中性粒细胞减少和过氧化氢酶处理的动物中，MCP-1 mRNA和蛋白的局部表达均降低，但在超氧化物歧化酶处理的大鼠中未降低。用H2O2或活化的中性粒细胞孵育的静止人脐静脉内皮细胞分泌MCP-1。这些数据表明，中性粒细胞和H2O2是葡聚糖输注后肉芽肿完全形成和早期血管壁相关MCP-1表达所必需的。这些体内数据，加上体外数据表明过氧化氢酶敏感试剂H2O2和中性粒细胞衍生的活性氧中间体（即H2O2）均可诱导人脐静脉内皮细胞分泌MCP-1，支持了中性粒细胞和中性粒细胞衍生产物（H2O2）通过诱导局部MCP-1表达影响肉芽肿形成的假说。
