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Oxycodone attenuates vascular leak and lung inflammation in a clinically relevant two-hit rat model of acute lung injury
Cytokine ( IF 3.7 ) Pub Date : 2021-02-01 , DOI: 10.1016/j.cyto.2020.155346 Xinyi Li 1 , Rui Li 2 , Qing Fang 1 , Muhammad Jamal 3 , Chengyao Wang 1 , Yanlin Wang 1 , Zongze Zhang 1 , Xiaojing Wu 4 , Xuemin Song 1
Cytokine ( IF 3.7 ) Pub Date : 2021-02-01 , DOI: 10.1016/j.cyto.2020.155346 Xinyi Li 1 , Rui Li 2 , Qing Fang 1 , Muhammad Jamal 3 , Chengyao Wang 1 , Yanlin Wang 1 , Zongze Zhang 1 , Xiaojing Wu 4 , Xuemin Song 1
Affiliation
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BACKGROUND
Oxycodone is a synthetic opioid receptor agonist that exerts antinociceptive activity via κ-, μ- and δ-opioid receptors (KOR, MOR and DOR, respectively). Activation of MOR has been reported to provide protection against acute lung injury (ALI). We hypothesized that pretreatment with oxycodone would attenuate lung injury at the level of alveolar tight junctions (TJs) and aquaporins (AQPs) and investigated this possibility in a two-hit model of ALI induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). METHOD
Male Sprague Dawley rats and A59 cells were divided into 6 groups: the control group, ALI group, oxycodone-pretreated group, and oxycodone/κ-, μ-, or δ-opioid receptor antagonist-pretreated groups. The rats were pretreated with oxycodone 30 min before intravenous injection of LPS and then allowed to recover for 24 h prior to MV, establishing a two-hit model of ALI. The cells were similarly treated with oxycodone (with or without antagonists) 30 min after exposure to lipopolysaccharide. The cells were cyclically stretched 24 h later to mirror the in vivo MV protocol. RESULTS
Oxycodone alleviated the histological lung changes in the rats with ALI and decreased pulmonary microvascular permeability both in vivo and in vitro. Oxycodone upregulated the expression of claudin-5, ZO-1, AQP1, and AQP5 but downregulated the expression of TNF-α, IL-1β, TLR4, NF-κB, MMP9, and caspase-3 and suppressed endothelial apoptosis in vivo and in vitro. These protective effects of oxycodone were partly eliminated by KOR and MOR antagonists but not by DOR antagonists. CONCLUSION
Oxycodone pretreatment appears to act via κ- and μ-opioid receptors to ameliorate LPS- and MV-induced lung injury by suppressing inflammation and apoptosis, and this protective effect might be mediated through the inhibition of the TLR4/NF-κB pathways.
中文翻译：
羟考酮减轻临床相关的急性肺损伤两次打击大鼠模型中的血管渗漏和肺部炎症
背景技术羟考酮是一种合成的阿片受体激动剂，通过κ-、μ-和δ-阿片受体（分别为KOR、MOR和DOR）发挥镇痛活性。据报道，激活 MOR 可提供针对急性肺损伤 (ALI) 的保护。我们假设用羟考酮预处理会减轻肺泡紧密连接 (TJs) 和水通道蛋白 (AQPs) 水平的肺损伤，并在脂多糖 (LPS) 和机械通气 (MV) 诱导的 ALI 二次打击模型中研究了这种可能性。方法雄性Sprague Dawley大鼠和A59细胞分为6组：对照组、ALI组、羟考酮预处理组和羟考酮/κ-、μ-或δ-阿片受体拮抗剂预处理组。大鼠在静脉注射LPS前30分钟用羟考酮预处理，然后在MV前恢复24小时，建立ALI的二次打击模型。细胞在暴露于脂多糖后 30 分钟用羟考酮（有或没有拮抗剂）类似地处理。细胞在 24 小时后循环拉伸以反映体内 MV 方案。结果羟考酮在体内外均能减轻ALI大鼠肺组织学改变，降低肺微血管通透性。羟考酮上调 claudin-5、ZO-1、AQP1 和 AQP5 的表达，但下调 TNF-α、IL-1β、TLR4、NF-κB、MMP9 和 caspase-3 的表达，并在体内和体内抑制内皮细胞凋亡体外。羟考酮的这些保护作用被 KOR 和 MOR 拮抗剂部分消除，但不被 DOR 拮抗剂消除。结
更新日期：2021-02-01
中文翻译：
羟考酮减轻临床相关的急性肺损伤两次打击大鼠模型中的血管渗漏和肺部炎症
背景技术羟考酮是一种合成的阿片受体激动剂，通过κ-、μ-和δ-阿片受体（分别为KOR、MOR和DOR）发挥镇痛活性。据报道，激活 MOR 可提供针对急性肺损伤 (ALI) 的保护。我们假设用羟考酮预处理会减轻肺泡紧密连接 (TJs) 和水通道蛋白 (AQPs) 水平的肺损伤，并在脂多糖 (LPS) 和机械通气 (MV) 诱导的 ALI 二次打击模型中研究了这种可能性。方法雄性Sprague Dawley大鼠和A59细胞分为6组：对照组、ALI组、羟考酮预处理组和羟考酮/κ-、μ-或δ-阿片受体拮抗剂预处理组。大鼠在静脉注射LPS前30分钟用羟考酮预处理，然后在MV前恢复24小时，建立ALI的二次打击模型。细胞在暴露于脂多糖后 30 分钟用羟考酮（有或没有拮抗剂）类似地处理。细胞在 24 小时后循环拉伸以反映体内 MV 方案。结果羟考酮在体内外均能减轻ALI大鼠肺组织学改变，降低肺微血管通透性。羟考酮上调 claudin-5、ZO-1、AQP1 和 AQP5 的表达，但下调 TNF-α、IL-1β、TLR4、NF-κB、MMP9 和 caspase-3 的表达，并在体内和体内抑制内皮细胞凋亡体外。羟考酮的这些保护作用被 KOR 和 MOR 拮抗剂部分消除，但不被 DOR 拮抗剂消除。结
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