Heat-shock response increases lung injury caused by Pseudomonas aeruginosa via an interleukin-10-dependent mechanism in mice.
Heat-shock response increases lung injury caused by Pseudomonas aeruginosa via an interleukin-10-dependent mechanism in mice.
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DOI：
10.1097/aln.0000000000000235
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发表时间：
2014-06
期刊：
影响因子：
8.8
通讯作者：
Pittet JF
中科院分区：
文献类型：
--
作者：
Carles M;Wagener BM;Lafargue M;Roux J;Iles K;Liu D;Rodriguez CA;Anjum N;Zmijewski J;Ricci JE;Pittet JF
热休克反应（HSR）通过抑制无菌炎症激活的信号通路来防止缺血再灌注损伤等损伤。然而，HSR 激活调节肺损伤和宿主对细菌性肺部感染的反应的机制仍不清楚。 24小时后，肺部注入铜绿假单胞菌（P.）的小鼠（每个实验组至少六只小鼠）通过全身热疗或腹腔注射格尔德霉素激活HSR。滴注后四小时，测量肺内皮和上皮通透性、细菌计数、支气管肺泡灌洗液中的蛋白质水平和肺髓过氧化物酶活性。记录铜绿假单胞菌滴注后24小时的死亡率。还检查了 HSR 对白介素 (IL)-10 释放和小鼠肺泡巨噬细胞系杀灭铜绿假单胞菌以及中性粒细胞吞噬作用的影响。 HSR 激活使肺内皮 (42%) 和上皮对蛋白质的通透性 (50%) 恶化，肺细菌清除率降低 (71%) 降低，并增加与铜绿假单胞菌肺炎相关的死亡率 (50%)，这种效应在 Hsp72 缺失小鼠中未观察到。 HSR 介导的中性粒细胞吞噬作用 (69%) 和巨噬细胞杀灭细菌 (38%) 的减少是 IL-10 依赖性的，这一机制已通过热休克 IL-10 缺失小鼠中铜绿假单胞菌肺炎引起的肺部细菌清除率增加和死亡率降低 (70%) 得到证实。先前的 HSR 激活通过 Hsp72 和 IL-10 依赖性机制加重小鼠铜绿假单胞菌肺炎相关的肺损伤。这些结果为严重创伤后观察到的免疫抑制提供了一种新机制，已知该机制可激活人类的 HSR。
The heat shock response (HSR) protects from insults, such as ischemia-reperfusion injury, by inhibiting signaling pathways activated by sterile inflammation. However, the mechanisms by which the HSR activation would modulate lung damage and host response to a bacterial lung infection remain unknown. HSR was activated with whole body hyperthermia or by intraperitoneal geldanamycin in mice that had their lungs instilled with Pseudomonas (P.) aeruginosa 24 h later (at least six mice per experimental group). Four hours after instillation, lung endothelial and epithelial permeability, bacterial counts, protein levels in bronchoalveolar lavage fluid and lung myeloperoxidase activity were measured. Mortality rate 24 h after P. aeruginosa instillation was recorded. The HSR effect on the release of interleukin (IL)-10 and killing of P. aeruginosa bacteria by a mouse alveolar macrophage cell line and on neutrophil phagocytosis was also examined. HSR activation worsened lung endothelial (42%) and epithelial permeability (50%) to protein, decreased lung bacterial clearance (71%) and increased mortality (50%) associated with P. aeruginosa pneumonia, an effect that was not observed in Hsp72 null mice. HSR-mediated decrease in neutrophil phagocytosis (69%) and bacterial killing (38%) by macrophages was IL-10-dependent, a mechanism confirmed by increased lung bacterial clearance and decreased mortality (70%) caused by P. aeruginosa pneumonia in heat-shocked IL-10 null mice. Prior HSR activation worsens lung injury associated with P. aeruginosa pneumonia in mice via Hsp72 and IL-10-dependent mechanisms. These results provide a novel mechanism for the immunosuppression observed after severe trauma that is known to activate HSR in humans.