Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury
Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury
复制标题
DOI：
10.1152/physiolgenomics.00291.2004
复制
发表时间：
2005-04-14
影响因子：
4.6
通讯作者：
Malik, AB
中科院分区：
文献类型：
--
作者：
Gao, XP;Liu, QH;Malik, AB
为了长期灭活 β(2)-整合素 CD11b (Mac-1)，我们在小鼠中制作了转基因模型，在其中表达 CD11b 拮抗剂多肽中性粒细胞抑制因子 (NIF)。使用这些小鼠，我们确定了 CD11b 失活对多形核白细胞 (PMN) 功能和大肠杆菌败血症诱导的急性肺损伤 (ALI) 的体内影响。在野生型 PMN 中，大肠杆菌攻击后 1 小时内诱导 CD11b 表达，而在 NIF+/+ PMN 中这种反应显着降低。免疫共沉淀研究表明，NIF 与 NIF+/+ PMN 中的 CD11b 相关。为了验证 CD11b 阻断的有效性，我们比较了 NIF+/+ 和 Mac-1 缺陷 (Mac-1(-/-)) 小鼠的 PMN 功能。 Mac-1(-/-) 和 NIF+/+ PMN 对 LPS 的反应对内皮细胞的粘附在两种类型的 PMN 中均降低，并且仅通过添加抗 CD11a 单克隆抗体即可完全阻断。这一发现表明 NIF+/+ PMN 中 CD11a 功能完整，但 CD11b 功能被阻断。 NIF-/-小鼠中CD11b失活可干扰大肠杆菌诱导的肺中性粒细胞浸润，并阻止肺微血管通透性增加和水肿形成，大部分保护作用在大肠杆菌感染后1小时内可见。因此，我们的结果表明，CD11b 在革兰氏阴性败血症早期介导肺中性粒细胞隔离和血管损伤中发挥着至关重要的作用。 NIF+/+ 小鼠模型中 CD11b 通过与 NIF 结合而失活，是体内评估 PMN CD11b 在血管炎症机制中作用的潜在有用模型。
To inactivate chronically the beta(2)-integrin CD11b (Mac-1), we made a transgenic model in mice in which we expressed the CD11b antagonist polypeptide neutrophil inhibitory factor (NIF). Using these mice, we determined the in vivo effects of CD11b inactivation on polymorphonuclear leukocyte (PMN) function and acute lung injury (ALI) induced by Escherichia coli septicemia. In wild-type PMNs, CD11b expression was induced within 1 h after E. coli challenge, whereas this response was significantly reduced in NIF+/+ PMNs. Coimmunoprecipitation studies showed that NIF associated with CD11b in NIF+/+ PMNs. To validate the effectiveness of CD11b blockade, we compared PMN function in NIF+/+ and Mac-1-deficient (Mac-1(-/-)) mice. Adhesion of both Mac-1(-/-) and NIF+/+ PMNs to endothelial cells in response to LPS was reduced in both types of PMNs and fully blocked only by the addition of anti-CD11a monoclonal antibody. This finding is indicative of intact CD11a function in the NIF+/+ PMNs but the blockade of CD11b function. CD11b inactivation in NIF-/- mice interfered with lung PMN infiltration induced by E. coli and prevented the increase in lung microvessel permeability and edema formation, with most of the protection seen in the 1-h period after the E. coli. Thus our results demonstrate that CD11b plays a crucial role in mediating lung PMN sequestration and vascular injury in the early phase of gram-negative septicemia. The NIF+/+ mouse model, in which CD11b is inactivated by binding to NIF, is a potentially useful model for in vivo assessment of the role of PMN CD11b in the mechanism of vascular inflammation.