Jiang Yuan-Xu, Huang Ze-Wei
Department of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The Fist Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong Province, 518020, P.R. China.
Department of Critical Care Medicine, Shenzhen People's Hospital, Shenzhen, Guangdong Province, 518020, P.R. China.
Iran J Basic Med Sci. 2022 Aug;25(8):1002-1008. doi: 10.22038/IJBMS.2022.64655.14230.
Previous studies have shown that ulinastatin (UTI) alleviates pulmonary edema in acute lung injury (ALI) caused by lipopolysaccharide (LPS), although the mechanism behind this action is uncertain. This research aimed to identify the fundamental mechanism by which UTI alleviates pulmonary edema.
We established a model of acute lung injury (ALI) in rats by using LPS as the inciting agent.The control, LPS, and LPS+UTI groups were each comprised of a specific number of randomly selected Wistar rats. We evaluated lung injury and determined pulmonary edema. The concentrations of TNF-α, IL-1β and IL-6 in BALF and the expression levels of α1Na, k-ATPase, β1Na, K-AtPase, α-ENaC, β-ENaC, γ-ENaC, Zonula occludens (ZO)-1, Occludin, Caludin-5, PI3K, Akt, TLR4, MyD88 and NF-ƘBwere identified in lung tissues.
The presence of UTI was associated with a reduction in lung pathological alterations, lung injury scores, the lung W/D ratio, and MPO activity, in addition to the improved gas exchange (P<0.01). Furthermore, UTI alleviated EB leakage and stimulated AFC (<0.01). Importantly, UTI increased the expression of ZO-1, Occludin, Caludin-5, α1Na, K-ATPase, β1Na, K-AtPase, α-ENaC, β-ENaC, and γ-ENaC (<0.01). Furthermore, UTI inhibited the inflammatory response, enhanced the expression of PI3K and Akt and hindered TLR4, MyD88, and NF-ƘB expression (<0.01) in lung tissues.
Our results demonstrated that UTI attenuated pulmonary edema by reducing pulmonary permeability and promoting AFC through inhibiting the inflammatory response, and the mechanism is related to promoting PI3K/Akt signaling pathways and suppressing TLR4/MyD88/NF-ƘB signaling pathways.
既往研究表明，乌司他丁（UTI）可减轻脂多糖（LPS）所致急性肺损伤（ALI）中的肺水肿，但其作用机制尚不清楚。本研究旨在确定UTI减轻肺水肿的基本机制。
我们以LPS作为诱发剂建立大鼠急性肺损伤（ALI）模型。对照组、LPS组和LPS + UTI组每组均由特定数量的随机选取的Wistar大鼠组成。我们评估了肺损伤并测定了肺水肿情况。检测了支气管肺泡灌洗液（BALF）中TNF-α、IL-1β和IL-6的浓度以及肺组织中α1Na，k-ATP酶、β1Na，K-ATP酶、α-ENaC、β-ENaC、γ-ENaC、紧密连接蛋白（ZO）-1、闭合蛋白、Claudin-5、PI3K、Akt、TLR4、MyD88和NF-κB的表达水平。
UTI的存在与肺病理改变、肺损伤评分、肺湿干重比和髓过氧化物酶（MPO）活性的降低相关，同时气体交换得到改善（P<0.01）。此外，UTI减轻了伊文思蓝（EB）渗漏并促进了肺泡灌洗清除率（AFC）（P<0.01）。重要的是，UTI增加了ZO-1、闭合蛋白、Claudin-5、α1Na，K-ATP酶、β1Na，K-ATP酶、α-ENaC、β-ENaC和γ-ENaC的表达（P<0.01）。此外，UTI抑制了炎症反应，增强了PI3K和Akt的表达，并抑制了肺组织中TLR4、MyD88和NF-κB的表达（P<0.01）。
我们的结果表明，UTI通过抑制炎症反应降低肺通透性并促进AFC，从而减轻肺水肿，其机制与促进PI3K/Akt信号通路和抑制TLR4/MyD88/NF-κB信号通路有关。
