Yum H K, Arcaroli J, Kupfner J, Shenkar R, Penninger J M, Sasaki T, Yang K Y, Park J S, Abraham E
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
J Immunol. 2001 Dec 1;167(11):6601-8. doi: 10.4049/jimmunol.167.11.6601.
Activated neutrophils contribute to the development and severity of acute lung injury (ALI). Phosphoinositide 3-kinases (PI3-K) and the downstream serine/threonine kinase Akt/protein kinase B have a central role in modulating neutrophil function, including respiratory burst, chemotaxis, and apoptosis. In the present study, we found that exposure of neutrophils to endotoxin resulted in phosphorylation of Akt, activation of NF-kappaB, and expression of the proinflammatory cytokines IL-1beta and TNF-alpha through PI3-K-dependent pathways. In vivo, endotoxin administration to mice resulted in activation of PI3-K and Akt in neutrophils that accumulated in the lungs. The severity of endotoxemia-induced ALI was significantly diminished in mice lacking the p110gamma catalytic subunit of PI3-K. In PI3-Kgamma(-/-) mice, lung edema, neutrophil recruitment, nuclear translocation of NF-kappaB, and pulmonary levels of IL-1beta and TNF-alpha were significantly lower after endotoxemia as compared with PI3-Kgamma(+/+) controls. Among neutrophils that did accumulate in the lungs of the PI3-Kgamma(-/-) mice after endotoxin administration, activation of NF-kappaB and expression of proinflammatory cytokines was diminished compared with levels present in lung neutrophils from PI3-Kgamma(+/+) mice. These results show that PI3-K, and particularly PI3-Kgamma, occupies a central position in regulating endotoxin-induced neutrophil activation, including that involved in ALI.
活化的中性粒细胞会促使急性肺损伤（ALI）的发生与加重。磷脂酰肌醇3激酶（PI3-K）及其下游的丝氨酸/苏氨酸激酶Akt/蛋白激酶B在调节中性粒细胞功能方面发挥着核心作用，这些功能包括呼吸爆发、趋化作用和细胞凋亡。在本研究中，我们发现中性粒细胞暴露于内毒素会导致Akt磷酸化、NF-κB激活，并通过PI3-K依赖途径促使促炎细胞因子IL-1β和TNF-α表达。在体内，给小鼠注射内毒素会导致肺中聚集的中性粒细胞内PI3-K和Akt激活。在缺乏PI3-K的p110γ催化亚基的小鼠中，内毒素血症诱导的ALI严重程度显著降低。在内毒素血症后，与PI3-Kγ(+/+)对照小鼠相比，PI3-Kγ(-/-)小鼠的肺水肿、中性粒细胞募集、NF-κB核转位以及肺中IL-1β和TNF-α水平均显著降低。在内毒素给药后确实在PI3-Kγ(-/-)小鼠肺中聚集的中性粒细胞中，与PI3-Kγ(+/+)小鼠肺中性粒细胞中的水平相比，NF-κB激活和促炎细胞因子表达均有所减少。这些结果表明，PI3-K，尤其是PI3-Kγ，在调节内毒素诱导的中性粒细胞激活（包括与ALI相关的激活）中占据核心地位。
