Department of Anesthesiology, Affiliated Shenzhen Maternity & Child Healthcare Hospital, Southern Medical University, Shenzhen 518028, China.
Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
Oxid Med Cell Longev. 2021 Dec 29;2021:8302831. doi: 10.1155/2021/8302831. eCollection 2021.
Intestinal ischemia is a common clinical critical illness. Intestinal ischemia-reperfusion (IIR) leads to acute lung injury (ALI), but the causative factors of ALI are unknown. The aim of this study was to reveal the causative factors and mechanisms of IIR-induced lung injury.
A mouse model of IIR was developed using C57BL/6 mice, followed by detection of lung injury status and plasma levels of inflammatory factors in sham-operated mice and model mice. Some model mice were treated with a tumor necrosis factor- (TNF-) inhibitor lenalidomide (10 mg/kg), followed by observation of lung injury status through hematoxylin and eosin staining and detection of neutrophil infiltration levels through naphthol esterase and Ly6G immunohistochemical staining. Additionally, peripheral blood polymorphonuclear neutrophils (PMNs) were cultured and then stimulated by TNF- to mimic inflammatory stimuli; this TNF- stimulation was also performed on PMNs after knockdown of FoxO3a or treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. PMN apoptosis after stimulation was detected using flow cytometry. Finally, the role of PMN apoptosis in IIR-induced lung injury was evaluated by detecting the ALI status in the model mice administered with ABT-199, a Bcl-2 inhibitor.
IIR led to pulmonary histopathological injury and increased lung water content, which were accompanied by increased plasma levels of inflammatory factors, with the TNF- plasma level showing the most pronounced increase. Inhibition of TNF- led to effective reduction of lung tissue injury, especially that of the damaging infiltration of PMNs in the lung. knockdown of FoxO3a or inhibition of JNK activity could inhibit TNF--induced PMN apoptosis. Further experiments revealed that ABT-199 effectively alleviated lung injury and decreased inflammation levels by promoting PMN apoptosis during IIR-induced lung injury.
TNF- activates the JNK/FoxO3a pathway to induce a delay in PMN apoptosis, which promotes IIR-induced lung injury.
肠缺血是一种常见的临床危重症。肠缺血再灌注（IIR）可导致急性肺损伤（ALI），但其致病因素尚不清楚。本研究旨在揭示 IIR 诱导肺损伤的致病因素和机制。
采用 C57BL/6 小鼠建立 IIR 模型，检测假手术组和模型组小鼠肺损伤状态和血浆中炎症因子水平。部分模型组小鼠给予 TNF-抑制剂来那度胺（10mg/kg）处理，通过苏木精-伊红染色观察肺损伤状态，萘酚酯酶和 Ly6G 免疫组化染色检测中性粒细胞浸润水平。此外，培养外周血多形核粒细胞（PMNs），用 TNF-刺激模拟炎症刺激，FoxO3a 敲低或 c-Jun N-末端激酶（JNK）抑制剂 SP600125 处理 PMNs 后，再用 TNF-刺激，用流式细胞术检测 PMN 凋亡。最后，通过检测给予 Bcl-2 抑制剂 ABT-199 的模型小鼠的 ALI 状态，评估 PMN 凋亡在 IIR 诱导肺损伤中的作用。
IIR 导致肺组织病理损伤和肺含水量增加，同时伴有炎症因子血浆水平升高，其中 TNF- 升高最明显。抑制 TNF-可有效减轻肺组织损伤，特别是肺内 PMN 的破坏性浸润。FoxO3a 敲低或 JNK 活性抑制可抑制 TNF-诱导的 PMN 凋亡。进一步实验发现，ABT-199 通过促进 IIR 诱导的肺损伤时的 PMN 凋亡，有效缓解肺损伤，降低炎症水平。
TNF- 激活 JNK/FoxO3a 通路，导致 PMN 凋亡延迟，促进 IIR 诱导的肺损伤。
