Postischemic treatment of namefene hydrochloride alleviates lung ischemia reperfusion injury by inhibiting TLR2/MyD88/NF- κB p65 inflammation pathway in rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

XU Biao ¹ , LI Wenhua ¹ , WU Wei ¹ , GAO Rui ¹ , HU Honglin ¹ ,  WANG Jiwu ²

1. Emergency Department, Wuhan No.4 Hospital, Wuhan, Hubei 430034, P. R. China;
2. Department of Cardiothoracic Surgery, Wuhan No.4 Hospital, Wuhan, Hubei 430034, P. R. China;

Corresponding author：

WANG Jiwu, Email: pytx110@126.com

Keywords：

Nalmefene hydrochloride; post-ischemic treatment; pulmonary ischemia-reperfusion injury; TLR2/MyD88/NF-κB p65

DOI：

10.7507/1671-6205.202304066

Video：

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Objective To study the mechanism of alleviating lung ischemia-reperfusion injury by postischemic treatment with namefene hydrochloride, and explore the optimal timing of drug treatment throughout the disease course. Methods A total of 60 rats were randomly divided into six groups with 10 rats in each group: a sham group, a model group, a nalmefene A (NA) group, a nalmefene B (NB) group, a nalmefene C (NC) group and a nalmefene D (ND) group. The sham group without drug treatment was not treated with ischemia-reperfusion. The lung ischemia-reperfusion model was established by occlusion of the left pulmonary hilum in the model group without drug treatment. After ischemic treatment, the NA, NB, NC and ND groups were respectively injected with nalmefene (15 μg/kg) by the tail vein at 5 min before, 10 min, 30 min and 60 min after pulmonary circulation reperfusion. At the 3^rd hour after reperfusion, all rats were sacrificed and the specimens from the upper lobe of the left lung tissue were preserved to observe pulmonary lesions, detect wet/dry weight ratio and the activity of myeloperoxidase (MPO), the expressions of tumor necrosis factor-α (TNF-α), Toll-like receptor 2 (TLR2) mRNA and MyD88 mRNA as well as the expressions of TLR2, MyD88, NF-κB p65 and p-NF-κB p65 in lung tissue. Results There were different degrees of alveolar septal destruction, obvious pulmonary interstitial edema, the infiltration of inflammatory cell, the exudationred of blood cell in the mesenchyme, and the collapse of partial alveolar in the model group and the NA, NB, NC, ND groups. In terms of wet/dry weight ratio, the score of lung tissue injury, the activity of MPO, the expressions of TNF-α, TLR2 mRNA and MyD88 mRNA as well as the expressions of TLR2, MyD88, NF-κB p65 and p-NF-κB p65 in lung tissue, the model group were significantly higher than the sham group (P<0.01); there was no significant difference between the ND group and the model group (P>0.05). The corresponding test values of the nalmefene groups with post-ischemic treatment showed the characteristics of ND group> NC group> NB group> NA group (P<0.01). Conclusion The effect of nammefene on alleviating lung ischemia-reperfusion injury is closely related to the inhibition of TLR2, MyD88, NF-κB p65 and phosphorylation of NF-κB p65 with a characteristic of time-dependent manner.

Citation： XU Biao, LI Wenhua, WU Wei, GAO Rui, HU Honglin, WANG Jiwu. Postischemic treatment of namefene hydrochloride alleviates lung ischemia reperfusion injury by inhibiting TLR2/MyD88/NF- κB p65 inflammation pathway in rats. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(6): 431-436. doi: 10.7507/1671-6205.202304066 Copy

1.	龙嘉琪, 李跃兵. 肺缺血再灌注损伤炎症与自噬相关性的研究进展. 实用医学杂志, 2022, 38(12): 1558-1562.
2.	Jungraithmayr W. Novel strategies for endothelial preservation in lung transplant ischemia-reperfusion injury. Front Physiol, 2020, 11: 581420.
3.	Dong LL, Yin LH, Li RM, et al. Dioscin alleviates lung ischemia/reperfusion injury by regulating FXR-mediated oxidative stress, apoptosis, and inflammation. Eur J Pharmacol, 2021, 908: 174321.
4.	Tian L, Yan J, Li K, et al. Ozone exposure promotes pyroptosis in rat lungs via the TLR2/4-NF-κB-NLRP3 signaling pathway. Toxicology, 2021, 450: 152668.
5.	Kong DL, Wang ZF, Tian J, et al. Glycyrrhizin inactivates toll-like receptor (TLR) signaling pathway to reduce lipopolysaccharide-induced acute lung injury by inhibiting TLR2. J Cell Physiol, 2019, 234(4): 4597-4607.
6.	Wu Z, Gu HY, Tian RH, et al. Efficacy of nalmefene with noninvasive positive-pressure ventilation on elderly patients with chronic obstructive pulmonary disease combining with type II respiratory failure. Am J Transl Res, 2021, 13(11): 12949-12956.
7.	Zhang NL, Wang HQ, Yang J, et al. Effects of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury. Eur Rev Med Pharmacol Sci, 2020, 24(1): 461-468.
8.	项冰倩, 颜王鑫, 高慧, 等. 右美托咪定通过抑制内质网过度应激减轻肺缺血–再灌注小鼠脑损伤. 中华急诊医学杂志, 2017, 26(11): 1260-1267.
9.	徐标, 李文华, 吴威. 盐酸纳美芬联合迷走神经电刺激对肺缺血–再灌注损伤大鼠肺组织强啡肽及IL-17的影响. 实用医学杂志, 2021, 37(22): 2851-2855.
10.	井军虎, 高晓玲, 仝惠民, 等. 吡啡尼酮对大鼠肺缺血再灌注损伤的保护作用及其机. 中华结核和呼吸杂志, 2021, 44(7): 624-627.
11.	Numata M, Voelker DR. Anti-inflammatory and anti-viral actions of anionic pulmonary surfactant phospholipids. Biochim Biophys Acta Mol Cell Biol Lipids, 2022, 1867(6): 159139.
12.	Lorenzo AD, Bolli E, Tarone L, et al. Toll-like receptor 2 at the crossroad between cancer cells, the immune system, and the microbiota. Int J Mol Sci, 2020, 21(24): 9418.
13.	Capece D, Verzella D, Flati I, et al. NF-κB: blending metabolism, immunity, and inflammation. Trends Immunol, 2022, 43(9): 757-775.
14.	Li F, Yao JH, Li L, et al. MiRNA-23a-5p is the biomarkers for gouty arthritis and promotes inflammation in rats of gouty arthritis via MyD88/NF-κB pathway by induction TLR2. Arch Rheumatol, 2022, 37(4): 536-546.
15.	Wang MZ, Wang LX, Fang L, et al. NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation. J Cell Physiol, 2019, 234(11): 19990-20001.
16.	Xue BB, Chen BH, Tang YN, et al. Dexmedetomidine protects against lung injury induced by limb ischemia-reperfusion via the TLR4/MyD88/NF-κB pathway. Kaohsiung J Med Sci, 2019, 35(11): 672-678.
17.	Chami B, Martin NJJ, Dennis JM, et al. Myeloperoxidase in the inflamed colon: a novel target for treating inflammatory bowel disease. Arch Biochem Biophys, 2018, 645: 61-71.
18.	Karki R, Kanneganti TD. The 'cytokine storm': molecular mechanisms and therapeutic prospects. Trends Immunol, 2021, 42(8): 681-705.
19.	Wang XS, Wang ZQ, Tang DH. Aerobic exercise alleviates inflammation, oxidative stress, and apoptosis in mice with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 2021, 16: 1369-1379.
20.	Bunte S, Behmenburg F, Majewski N, et al. Characteristics of dexmedetomidine postconditioning in the field of myocardial ischemia-reperfusion injury. Anesth Analg, 2020, 130(1): 90-98.
21.	Wu YS, Liu HQ, Wang XB, et al. Cardioprotection of pharmacological postconditioning on myocardial ischemia/reperfusion injury. Life Sci, 2021, 264: 118628.

1. 龙嘉琪, 李跃兵. 肺缺血再灌注损伤炎症与自噬相关性的研究进展. 实用医学杂志, 2022, 38(12): 1558-1562.
2. Jungraithmayr W. Novel strategies for endothelial preservation in lung transplant ischemia-reperfusion injury. Front Physiol, 2020, 11: 581420.
3. Dong LL, Yin LH, Li RM, et al. Dioscin alleviates lung ischemia/reperfusion injury by regulating FXR-mediated oxidative stress, apoptosis, and inflammation. Eur J Pharmacol, 2021, 908: 174321.
4. Tian L, Yan J, Li K, et al. Ozone exposure promotes pyroptosis in rat lungs via the TLR2/4-NF-κB-NLRP3 signaling pathway. Toxicology, 2021, 450: 152668.
5. Kong DL, Wang ZF, Tian J, et al. Glycyrrhizin inactivates toll-like receptor (TLR) signaling pathway to reduce lipopolysaccharide-induced acute lung injury by inhibiting TLR2. J Cell Physiol, 2019, 234(4): 4597-4607.
6. Wu Z, Gu HY, Tian RH, et al. Efficacy of nalmefene with noninvasive positive-pressure ventilation on elderly patients with chronic obstructive pulmonary disease combining with type II respiratory failure. Am J Transl Res, 2021, 13(11): 12949-12956.
7. Zhang NL, Wang HQ, Yang J, et al. Effects of nalmefene hydrochloride on TLR4 signaling pathway in rats with lung ischemia-reperfusion injury. Eur Rev Med Pharmacol Sci, 2020, 24(1): 461-468.
8. 项冰倩, 颜王鑫, 高慧, 等. 右美托咪定通过抑制内质网过度应激减轻肺缺血–再灌注小鼠脑损伤. 中华急诊医学杂志, 2017, 26(11): 1260-1267.
9. 徐标, 李文华, 吴威. 盐酸纳美芬联合迷走神经电刺激对肺缺血–再灌注损伤大鼠肺组织强啡肽及IL-17的影响. 实用医学杂志, 2021, 37(22): 2851-2855.
10. 井军虎, 高晓玲, 仝惠民, 等. 吡啡尼酮对大鼠肺缺血再灌注损伤的保护作用及其机. 中华结核和呼吸杂志, 2021, 44(7): 624-627.
11. Numata M, Voelker DR. Anti-inflammatory and anti-viral actions of anionic pulmonary surfactant phospholipids. Biochim Biophys Acta Mol Cell Biol Lipids, 2022, 1867(6): 159139.
12. Lorenzo AD, Bolli E, Tarone L, et al. Toll-like receptor 2 at the crossroad between cancer cells, the immune system, and the microbiota. Int J Mol Sci, 2020, 21(24): 9418.
13. Capece D, Verzella D, Flati I, et al. NF-κB: blending metabolism, immunity, and inflammation. Trends Immunol, 2022, 43(9): 757-775.
14. Li F, Yao JH, Li L, et al. MiRNA-23a-5p is the biomarkers for gouty arthritis and promotes inflammation in rats of gouty arthritis via MyD88/NF-κB pathway by induction TLR2. Arch Rheumatol, 2022, 37(4): 536-546.
15. Wang MZ, Wang LX, Fang L, et al. NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation. J Cell Physiol, 2019, 234(11): 19990-20001.
16. Xue BB, Chen BH, Tang YN, et al. Dexmedetomidine protects against lung injury induced by limb ischemia-reperfusion via the TLR4/MyD88/NF-κB pathway. Kaohsiung J Med Sci, 2019, 35(11): 672-678.
17. Chami B, Martin NJJ, Dennis JM, et al. Myeloperoxidase in the inflamed colon: a novel target for treating inflammatory bowel disease. Arch Biochem Biophys, 2018, 645: 61-71.
18. Karki R, Kanneganti TD. The 'cytokine storm': molecular mechanisms and therapeutic prospects. Trends Immunol, 2021, 42(8): 681-705.
19. Wang XS, Wang ZQ, Tang DH. Aerobic exercise alleviates inflammation, oxidative stress, and apoptosis in mice with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 2021, 16: 1369-1379.
20. Bunte S, Behmenburg F, Majewski N, et al. Characteristics of dexmedetomidine postconditioning in the field of myocardial ischemia-reperfusion injury. Anesth Analg, 2020, 130(1): 90-98.
21. Wu YS, Liu HQ, Wang XB, et al. Cardioprotection of pharmacological postconditioning on myocardial ischemia/reperfusion injury. Life Sci, 2021, 264: 118628.

Chinese Journal of Respiratory and Critical Care Medicine

Postischemic treatment of namefene hydrochloride alleviates lung ischemia reperfusion injury by inhibiting TLR2/MyD88/NF- κB p65 inflammation pathway in rats

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