Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines
Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines
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DOI：
10.1096/fj.03-1412fje
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发表时间：
2004-04-01
期刊：
影响因子：
4.8
通讯作者：
Kheradmand, F
中科院分区：
文献类型：
--
作者：
Corry, DB;Kiss, A;Kheradmand, F
引发过敏性肺部炎症的机制与哮喘等疾病的表达相关，但炎症消退的潜在因素同样重要。以前，我们证明了基质金属蛋白酶2（MMP 2）的重要性，气道流出的肺嗜酸性粒细胞，一个关键的抗炎机制，没有它的小鼠是高度敏感的致命窒息。在这里，我们表明，白细胞MMP 9是主要的气道基质金属蛋白酶控制炎症细胞的外流。MMP 9（-/-）小鼠的过敏性肺表型与WT相似，并且未因同时缺失MMP 2基因（双敲除; dko）而改变。然而，过敏原激发的MMP 9（-/-）和dko小鼠的肺中的炎症细胞异常积聚，支气管肺泡灌洗液中存在较少的嗜酸性粒细胞和中性粒细胞。这些异常的细胞运输模式被解释为跨上皮趋化因子梯度的破坏，在MMP 2（-/-）小鼠中仅影响嗜酸性粒细胞趋化因子（CCL 11），但在MMP 9（-/-）和dko小鼠中涉及嗜酸性粒细胞趋化因子、MARC（CCL 7）和TARC（CCL 17）。因此，通过建立多个跨上皮趋化因子梯度，MMP 9广泛参与过敏性炎症的消退，这是一种与MMP 2发挥的更有限作用重叠的重要保护机制。
The mechanisms that initiate allergic lung inflammation are relevant to expression of diseases such as asthma, but the factors underlying resolution of inflammation are equally important. Previously, we demonstrated the importance of matrix metalloproteinase 2 (MMP2) for airway egression of lung eosinophils, a critical anti-inflammatory mechanism without which mice are rendered highly susceptible to lethal asphyxiation. Here we show that leukocyte MMP9 is the dominant airway MMP controlling inflammatory cell egression. The allergic lung phenotype of MMP9(-/-) mice was similar to WT and was not altered by concomitant deletion of the MMP2 gene ( double knockout; dko). However, inflammatory cells accumulated aberrantly in the lungs of allergen-challenged MMP9(-/-) and dko mice and fewer eosinophils and neutrophils were present in bronchoalveolar lavage. These aberrant cellular trafficking patterns were explained by disruption of transepithelial chemokine gradients, in MMP2(-/-) mice affecting only eotaxin (CCL11), but in MMP9(-/-) and dko mice involving eotaxin, MARC (CCL7), and TARC (CCL17). Thus, by establishing multiple transepithelial chemokine gradients, MMP9 is broadly implicated in the resolution of allergic inflammation, an essential protective mechanism that overlaps with a more limited role played by MMP2.