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【文摘发布】磷脂酰肌醇-3激酶γ对宿主抗肺炎球
Author:Ulrich A. Maus
Abstract:
Rationale: The pivotal role of phosphoinositide 3-kinase (PI3K) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3K signaling might increase the risk of bacterial infections in humans.
Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3K would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae.
Methods: PI3K knockout (KO) and wild-type mice were infected with S. pneumoniae or challenged with the pneumococcal virulence factor pneumolysin (PLY), and inflammatory leukocyte recruitment, bacterial pathogen elimination, and resolution/repair processes were determined.
Measurements and Main Results: PI3K KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared with wild-type mice. S. pneumoniae–infected PI3K KO mice and wild-type mice pretreated with the pharmacologic inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than control animals. They also displayed a significantly reduced lung pneumococcal clearance and showed an impaired resolution/repair process, leading to progressive pneumococcal pneumonia.
Conclusions: PI3K gene deletion or pharmacologic inhibition of PI3K leads to perturbations of critical innate immune responses of the lung to challenge with S. pneumoniae. These data are of clinical relevance for the treatment of chronic inflammatory diseases where pharmacologic inhibition of PI3K signaling to attenuate effector cell recruitment may have implications for innate immune surveillance of remote organ systems.
Key Words: lung • infection • macrophage
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
No data are currently available addressing the role of phosphoinositide 3-kinase (PI3K) deletion or inhibition on the lung host defense to Streptococcus pneumoniae infection.
What This Study Adds to the Field
Blockade of PI3K activity suppresses effector cell recruitment, reduces lung pneumococcal clearance, and may have implications for the immune surveillance of distant organ systems.
American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 958-966, (2007)
本期AJRCCM封面文章
认领及参与讨论者方可pm我要全文 本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。 Titlemportance of Phosphoinositide 3-Kinase in the Host Defense against Pneumococcal Infection
题目： 磷酸肌醇3激酶（PI3K）在宿主抵抗肺炎球菌感染中的重要性
Author:Ulrich A. Maus
Abstract:
Rationale: The pivotal role of phosphoinositide 3-kinase (PI3K) in leukocyte recruitment makes it an attractive target for immunomodulatory therapy. However, interfering with PI3K signaling might increase the risk of bacterial infections in humans.
推理：由于PI3K在白细胞募集中具有关键作用，人们把它当作一个免疫调节治疗的靶点。但是干扰PI3K信号通路可能会增加患者细菌感染的机会。
Objectives: We hypothesized that deletion or pharmacologic inhibition of PI3K would impair the lung inflammatory response to the prototypic gram-positive bacterial pathogen Streptococcus pneumoniae.
目的：我们假设敲除或者药物抑制PI3K将损害肺脏对于革兰氏阳性菌肺炎链球菌的炎症反应。
Methods: PI3K knockout (KO) and wild-type mice were infected with S. pneumoniae or challenged with the pneumococcal virulence factor pneumolysin (PLY), and inflammatory leukocyte recruitment, bacterial pathogen elimination, and resolution/repair processes were determined.
方法：用肺炎球菌感染或者用肺炎球菌致病因子pneumolysin(PLY)刺激PI3K敲除鼠和野生型鼠，检测炎症导致的白细胞募集、病原体的清除、以及修复过程。
Measurements and Main Results: PI3K KO mice challenged with PLY responded with lung edema and neutrophilic alveolitis, but showed a drop in alveolar macrophages and failed to recruit exudate macrophages when compared with wild-type mice. S. pneumoniae–infected PI3K KO mice and wild-type mice pretreated with the pharmacologic inhibitor AS-605240 recruited similar numbers of neutrophils but substantially fewer exudate macrophages into their lungs than control animals. They also displayed a significantly reduced lung pneumococcal clearance and showed an impaired resolution/repair process, leading to progressive pneumococcal pneumonia.
检测数据和主要结果：PLY刺激PI3K敲除鼠会引起肺水肿和中心粒细胞肺泡炎，但是与野生型的小鼠相比较，其肺泡巨噬细胞数量减少、渗出液中无巨噬细胞。PI3K抑制剂AS-605240抑制肺炎球菌刺激的两种小鼠后，两者募集的中性白细胞在数量上相近，但是与正常对照相比，真正渗入肺脏的巨噬细胞很少。同时肺对肺炎球菌的清除明显减少，溶解修复过程也是减慢的，这些会引起肺炎的进一步恶化。
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作者:admin@医学,生命科学 2011-03-25 05:15
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