Role of phosphatidylinositol 3-kinase-γ in mediating lung neutrophil sequestration and vascular injury induced by E-coli sepsis
Role of phosphatidylinositol 3-kinase-γ in mediating lung neutrophil sequestration and vascular injury induced by E-coli sepsis
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DOI：
10.1152/ajplung.00179.2005
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发表时间：
2005-12-01
影响因子：
4.9
通讯作者：
Malik, AB
中科院分区：
文献类型：
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作者：
Ong, E;Gao, XP;Malik, AB
我们探讨了磷脂酰肌醇3-激酶-伽马(PI3K-伽马)在肺内多形核白细胞(PMN)隔离信号和炎性肺血管损伤机制中的作用。我们研究了PI3K-Gamma的p110催化亚单位缺失的小鼠(PI3K-Gamma(-/-)小鼠)。我们测量了肺组织中性粒细胞的隔离、微血管通透性和细菌血症后的水肿形成。经形态计量学评估，PI3K-γ(-/-)组小鼠肺间质中性粒细胞浸润在细菌攻击后1h内较对照组增加100%。PI3K-Gamma(-/-)小鼠在大肠杆菌攻击后，肺微血管通透性也有更大的增加，导致水肿形成。PI3K-Gamma(-/-)小鼠肺组织PMN滞留增加与PMN黏附蛋白CD47和β(3)-整合素表达增加有关。我们观察到，在大肠杆菌攻击后，PI3K-Gamma(-/-)小鼠肺中CD47和β(3)整合素与细胞外基质蛋白Vitronectin的相关性增加。这些小鼠的PMN还显示出β(3)-整合素的表达增加，并增强了β(3)-整合素依赖的PMN与Vitronectin的黏附。这些结果表明，在革兰氏阴性脓毒症中，PMN PI3K-伽马在负调控CD47和β(3)-整合素的表达中起着关键作用。大肠杆菌诱导的PMN中PI3K-γ的激活可能调节了继CD47和β(3)-整合素表达之后肺组织PMN的隔离程度。因此，PI3K-γ活化水平可能是PMN依赖性肺血管损伤的重要决定因素。
We addressed the in vivo role of phosphatidylinositol 3-kinase-gamma (PI3K-gamma) in signaling the sequestration of polymorphonuclear leukocytes (PMNs) in lungs and in the mechanism of inflammatory lung vascular injury. We studied mice with deletion of the p110 catalytic subunit of PI3K-gamma (PI3K-gamma(-/-) mice). We measured lung tissue PMN sequestration, microvascular permeability, and edema formation after bacteremia induced by intraperitoneal Escherichia coli challenge. PMN infiltration into the lung interstitium in PI3K-gamma(-/-) mice as assessed morphometrically was increased 100% over that in control mice within 1 h after bacterial challenge. PI3K-gamma(-/-) mice also developed a greater increase in lung microvascular permeability after E. coli challenge, resulting in edema formation. The augmented lung tissue PMN sequestration in PI3K-gamma(-/-) mice was associated with increased expression of the PMN adhesive proteins CD47 and beta(3)-integrins. We observed increased association of CD47 and beta(3)-integrins with the extracellular matrix protein vitronectin in lungs of PI3K-gamma(-/-) mice after E. coli challenge. PMNs from these mice also showed increased beta(3)-integrin expression and augmented beta(3)-integrin-dependent PMN adhesion to vitronectin. These results point to a key role of PMN PI3K-gamma in negatively regulating CD47 and beta(3)-integrin expression in gram-negative sepsis. PI3K-gamma activation in PMNs induced by E. coli may modulate the extent of lung tissue PMN sequestration secondary to CD47 and beta(3)-integrin expression. Therefore, the level of PI3K-gamma activation may be an important determinant of PMN-dependent lung vascular injury.