Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2013 Jun 15;190(12):6434-49. doi: 10.4049/jimmunol.1202329. Epub 2013 May 13.
To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyperresponsiveness (AHR), we compared AAI and AHR in wild-type (WT) versus Adam8(-/-) mice in different genetic backgrounds sensitized and challenged with OVA or house dust mite protein extract. OVA- and house dust mite-treated Adam8(-/-) mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some Th2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8's anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8(-/-) mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8(-/-) macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients, but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma.
为了确定解整合素金属蛋白酶 8（Adam8）是否调节过敏性气道炎症（AAI）和气道高反应性（AHR），我们比较了不同遗传背景下 OVA 或屋尘螨蛋白提取物致敏和激发的野生型（WT）与 Adam8（-/-）小鼠的 AAI 和 AHR。OVA 和屋尘螨处理的 Adam8（-/-）小鼠的肺白细胞计数更高，气道粘液化生更多，某些 Th2 细胞因子的肺水平更高，并且气道阻力对乙酰甲胆碱的增加幅度大于过敏原处理的 WT 小鼠。OVA 处理的 Adam8 骨髓嵌合体小鼠的研究证实，白细胞衍生的 Adam8 主要介导 Adam8 在小鼠气道中的抗炎活性。在具有 AAI 的 WT 小鼠中，气道嗜酸性粒细胞和巨噬细胞均表达 Adam8。Adam8 通过减少白细胞存活来限制 AAI 和 AHR，因为：1）与具有 AAI 的 WT 小鼠相比，具有 AAI 的 Adam8（-/-）小鼠的气道中凋亡的嗜酸性粒细胞和巨噬细胞更少；2）与 WT 白细胞相比，当细胞内在（而非外在）凋亡途径在体外被触发时，Adam8（-/-）巨噬细胞和嗜酸性粒细胞的凋亡率降低。ADAM8 在人类哮喘患者肺组织切片中的气道粒细胞中强烈表达，但令人惊讶的是，气道巨噬细胞的 ADAM8 染色比气道嗜酸性粒细胞少。因此，ADAM8 通过激活髓样白细胞中的内在凋亡途径，在小鼠的 AAI 中具有抗炎活性。增加髓样白细胞中 ADAM8 水平的策略可能在哮喘中有治疗功效。
