Time-dependent inhibition of immune complex-induced lung injury by catalase: relationship to alterations in macrophage and neutrophil matrix metalloproteinase elaboration.
Time-dependent inhibition of immune complex-induced lung injury by catalase: relationship to alterations in macrophage and neutrophil matrix metalloproteinase elaboration.
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过氧化氢酶对免疫复合物诱导的肺损伤的时间依赖性抑制：与巨噬细胞和中性粒细胞基质金属蛋白酶变化的关系。
DOI：
10.1016/s0891-5849(00)00282-3
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发表时间：
2000
影响因子：
7.4
通讯作者：
Varani,J
中科院分区：
文献类型：
--
作者：
Warner,RL;Bless,NM;Lewis,CS;Younkin,E;Beltran,L;Guo,R;Johnson,KJ;Varani,J
采用肺泡内牛血清白蛋白（BSA）和抗BSA IgG免疫复合物致大鼠急性肺损伤的方法。在这种损伤模型中，发生补体激活，大量中性粒细胞侵入肺泡和肺泡腔。在本研究中，动物进行了治疗与intraperheal过氧化氢酶伴随抗BSA或5-120分钟的滞后期后。过氧化氢酶治疗在时间为零或在5分钟后损伤未能防止肺损伤所示的渗透性变化，组织学特征，和中性粒细胞流入。然而，延迟15-30分钟（但不是120分钟）后的治疗提供了实质性的保护。与过去的发现一致[19]，肺损伤伴随着基质金属蛋白酶9（MMP-9）在支气管肺泡灌洗液（BAL）中的积聚。损伤的抑制和MMP-9水平的降低之间有很强的相关性。平行进行的体外研究显示，未受刺激的肺泡巨噬细胞不产生可测量的MMP-9，而在暴露于体内引发损伤的相同免疫复合物后有较大的诱导。MMP-2在相同条件下也略有上调。伴随处理过氧化氢酶极大地抑制MMP-9的巨噬细胞的生产，在响应免疫复合物，但这种治疗的基础生产的MMP-9或MMP-2的巨噬细胞几乎没有影响。抑制MMP-9表达的相同浓度的过氧化氢酶也抑制肿瘤坏死因子α的产生。相反，当中性粒细胞用过氧化氢酶处理，然后暴露于免疫复合物时，抗氧化剂未能阻止MMP-2或MMP-9的释放。综上所述，这些发现表明，抗氧化剂治疗干扰了肺泡巨噬细胞对MMPs的表达。对肺损伤的保护与BAL液中MMP水平的降低相关。
Rats were subjected to acute lung injury by the intra-alveolar formation of IgG immune complexes of bovine serum albumin (BSA) and anti-BSA. In this model of injury, complement activation occurs and large numbers of neutrophils invade the interstitium and alveolar space. In the present study, animals were treated with intratracheal catalase concomitantly with anti-BSA or after a lag period of 5–120 min. Catalase treatment at time-zero or at 5 min post injury failed to prevent lung injury as indicated by permeability change, histological features, and neutrophil influx. However, treatment after a delay of 15–30 min (but not 120 min) afforded substantial protection. Consistent with past findings [19], lung injury was accompanied by an accumulation of matrix metalloproteinase 9 (MMP-9) in bronchoalveolar lavage (BAL) fluid. There was a strong correlation between inhibition of injury and reduction in MMP-9 levels. In vitro studies conducted in parallel revealed that unstimulated alveolar macrophages did not produce measurable MMP-9, while there was a large induction following exposure to the same immune complexes that initiated injury in vivo. MMP-2 was also slightly upregulated under the same conditions. Concomitant treatment with catalase greatly inhibited MMP-9 production by macrophages in response to immune complexes, but this treatment had little effect on basal production of either MMP-9 or MMP-2 by macrophage. The same concentration of catalase that suppressed MMP-9 elaboration also inhibited the production of tumor necrosis factor α. In contrast, when neutrophils were treated with catalase and then exposed to immune complexes, the antioxidant failed to prevent the release of either MMP-2 or MMP-9. Taken together, these findings demonstrate that antioxidant treatment interferes with elaboration of MMPs by alveolar macrophages. Protection against lung injury is correlated with reduction in MMP levels in the BAL fluid.