Research progress on signal pathways in pathogenesis of acute lung injury and the drug intervention_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

YANG Sihao ¹ , NIE Hongxin ² ,  MENG Hui ¹

1. Department of Cardiothoracic Surgery, The Fifth Affiliated Hospital of Zunyi Medical University, Zhuhai, 519100, Guangdong,P. R. China;
2. Department of Emergency, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, Liaoning, P. R. China;

Corresponding author：

MENG Hui, Email: mhgl2008@163.com

Keywords：

Acute lung injury; signal pathway; inflammatory reaction; oxidative stress; review

DOI：

10.7507/1007-4848.202211068

Video：

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Abstract Full text Figures/Tables Video References Cited by

Acute lung injury (ALI), in which various factors inside and outside the lung lead to hypoxemic respiratory insufficiency and even the development of acute respiratory distress syndrome, has a high morbidity and mortality rate, and its pathogenesis is characterized by complex signaling pathways and limited therapeutic options. A large number of studies have reported that nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), vascular endothelial growth factors (VEGF) and JAK/signal transducer and activator of transcription (STAT) signaling pathways are all related to the inflammatory response of ALI, and they are involved in regulating the inflammatory response process of ALI individually or cooperatively. Therefore, this article reviews the research progress on the pathogenesis-related signaling pathways and the drug interventions, aiming to provide a reference for early intervention in lung injury, optimizing the donor pool to increase the proportion of donation after cardiac death and providing quality donor protection conditions.

Citation： YANG Sihao, NIE Hongxin, MENG Hui. Research progress on signal pathways in pathogenesis of acute lung injury and the drug intervention. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2024, 31(9): 1356-1362. doi: 10.7507/1007-4848.202211068 Copy

1.	Luan G, Pan F, Bu L, et al. Butorphanol promotes macrophage phenotypic transition to inhibit inflammatory lung injury via κ receptors. Front Immunol, 2021, 12: 692286.
2.	Arora S, Dev K, Agarwal B, et al. Macrophages: Their role, activation and polarization in pulmonary diseases. Immunobiology, 2018, 223(4): 383-396.
3.	Wu G, Zhu Q, Zeng J, et al. Extracellular mitochondrial DNA promote NLRP3 inflammasome activation and induce acute lung injury through TLR9 and NF-κB. J Thorac Dis, 2019, 11(11): 4816-4828.
4.	Du ZA, Sun MN, Hu ZS. Saikosaponin a ameliorates LPS-induced acute lung injury in mice. Inflammation, 2018, 41(1): 193-198.
5.	Huang X, Liu W, Zhou Y, et al. Dihydroartemisinin attenuates lipopolysaccharide-induced acute lung injury in mice by suppressing NF-κB signaling in an Nrf2-dependent manner. Int J Mol Med, 2019, 44(6): 2213-2222.
6.	Hu X, Liu S, Zhu J, et al. Dachengqi decoction alleviates acute lung injury and inhibits inflammatory cytokines production through TLR4/NF‐κB signaling pathway in vivo and in vitro. J Cell Biochem, 2019, 120(6): 8956-8964.
7.	Feng T, Zhou L, Gai S, et al. Acacia catechu (L. f. ) Willd and Scutellaria baicalensis Georgi extracts suppress LPS‐induced pro‐inflammatory responses through NF‐кB, MAPK, and PI3K‐Akt signaling pathways in alveolar epithelial type Ⅱ cells. Phytother Res, 2019, 33(12): 3251–3260.
8.	Li L, Chen J, Lin L, et al. Quzhou fructus aurantii extract suppresses inflammation via regulation of MAPK, NF-κB, and AMPK signaling pathway. Sci Rep, 2020, 10(1): 1593.
9.	Jin M, Feng H, Wang Y, et al. Gentiopicroside ameliorates oxidative stress and lipid accumulation through nuclearfactor erythroid 2-related factor 2 activation. Oxid Med Cell Longev, 2020, 2020: 2940746.
10.	Sokolowska M, Quesniaux VFJ, Akdis CA, et al. Acute respiratory barrier disruption by ozone exposure in mice. Front Immunol, 2019, 10: 2169.
11.	Li R, Zou X, Huang H, et al. HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of acute lung injury by regulating the maturation and function of dendritic cells. Front Immunol, 2020, 11: 1104.
12.	吴艳, 张铭, 鲁开智, 等. 腺苷A2b受体激活减轻小鼠肾缺血再灌注致肺损伤. 基础医学与临床, 2019, 39(8): 1102-1107.Wu Y, Zhang M, Lu KZ, et al. Adenosine A2b receptor activation attenuates lung injury induced by renal ischemia-reperfusion in mice. Basic Clin Med, 2019, 39(8): 1102-1107.
13.	Huppert LA, Matthay MA. Alveolar fluid clearance in pathologically relevant conditions: In vitro and in vivo models of acute respiratorydistress syndrome. Front Immunol, 2017, 8: 371.
14.	Yang J, Li M, Hu X, et al. Protectin DX promotes epithelial injury repair and inhibits fibroproliferation partly via ALX/PI3K signalling pathway. J Cell Mol Med, 2020, 24(23): 14001-14012.
15.	Hu X, Xu Q, Wan H, et al. PI3K-Akt-mTOR/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis. Lab Invest, 2020, 100(6): 801-811.
16.	Shi J, Yu J, Zhang Y, et al. PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury. Lab Invest, 2019, 99(12): 1795-1809.
17.	Yao M, Li F, Xu L, et al. 24-dehydrocholesterol reductase alleviates oxidative damage-induced apoptosis in alveolar epithelial cells via regulating phosphatidylinositol-3-kinase/protein kinase B activation. Bioengineered, 13(1): 155-163.
18.	Zhang Z, Zhou Y, Cao J, et al. Rosmarinic acid ameliorates septic-associated mortality and lung injury in mice via GRP78/IRE1α/JNK pathway. J Pharm Pharmacol, 2021, 73(7): 916-921.
19.	Zhang Z, Zhang L, Zhou L, et al. Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress. Redox Biol, 2019, 25: 101047.
20.	董超, 李华宇, 区豪杰, 等. 非诺贝特改善脂多糖诱导的急性肺损伤及其机制研究. 天津医药, 2022, 50(1): 59-66.Dong C, Li HY, Qu HJ, et al. Fenofibrate improves acute lung injury induced by lipopolysaccharide. Tianjin Med J, 2022, 50(1): 59-66.
21.	Hui Z, Jie H, Fan GH. Expression of DUSP12 reduces lung vascular endothelial cell damage in a murine model of lipopolysaccharide-induced acute lung injury via the apoptosis signal-regulating kinase 1 (ASK1)-Jun N-terminal kinase activation (JNK) pathway. Med Sci Monit, 2021, 27: e930429.
22.	Liu S, Su X, Pan P, et al. Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury. Sci Rep, 2016, 6: 37252.
23.	Ding J, Zhang Z, Huang W, et al. Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in LPS-induced neutrophil extracellular traps. Microbiol Immunol, 2021, 65(7): 257-264.
24.	Yang C, Song C, Liu Y, et al. Re-Du-Ning injection ameliorates LPS-induced lung injury through inhibiting neutrophil extracellular traps formation. Phytomedicine, 2021, 90: 153635.
25.	Li D, Pan L, Zhang X, et al. Lower oligomeric form of surfactant protein D in murine acute lung injury induces M1 subtype macrophages through calreticulin/p38 MAPK signaling pathway. Front Immunol, 2021, 12: 687506.
26.	Ding Q, Zhu W, Diao Y, et al. Elucidation of the mechanism of action of ginseng against acute lung injury/acute respiratory distress syndrome by a network pharmacology-based strategy. Front Pharmacol, 2020, 11: 611794.
27.	Zheng D, Liwinski T, Elinav E. Inflammasome activation and regulation: Toward a better understanding of complex mechanisms. Cell Discovery, 2020, 6(1): 36.
28.	Song W, Wei L, Du Y, et al. Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-κB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Int Immunopharmacol, 2018, 63: 227-238.
29.	Abd El-Fattah EE, Saber S, Mourad AAE, et al. The dynamic interplay between AMPK/NFκB signaling and NLRP3 is a new therapeutic target in inflammation: Emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury. Biomed Pharmacother, 2022, 147: 112628.
30.	He Y, Xu K, Wang Y, et al. AMPK as a potential pharmacological target for alleviating LPS-induced acute lung injury partly via NLRC4 inflammasome pathway inhibition. Exp Gerontol, 2019, 125: 110661.
31.	Kosztelnik M, Kurucz A, Papp D, et al. Suppression of AMPK/AAK-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress. FASEB J, 2019, 33(2): 2372-2387.
32.	Huang XT, Liu W, Zhou Y, et al. Galectin-1 ameliorates lipopolysaccharide-induced acute lung injury via AMPK-Nrf2 pathway in mice. Free Radic Biol Med, 2020, 146: 222-233.
33.	Dong W, He B, Qian H, et al. RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury. Autophagy, 2018, 14(10): 1677-1692.
34.	Kong X, Lin D, Lu L, et al. Apelin-13-mediated AMPK ameliorates endothelial barrier dysfunction in acute lung injury mice via improvement of mitochondrial function and autophagy. Int Immunopharmacol, 2021, 101(Pt B): 108230.
35.	Fu C, Hao S, Xu X, et al. Activation of SIRT1 ameliorates LPS-induced lung injury in mice via decreasing endothelial tight junction permeability. Acta Pharmacol Sin, 2019, 40(5): 630-641.
36.	Li X, Jamal M, Guo P, et al. Irisin alleviates pulmonary epithelial barrier dysfunction in sepsis-induced acute lung injury via activation of AMPK/SIRT1 pathways. Biomed Pharmacother, 2019, 118: 109363.
37.	Laddha AP, Kulkarni YA. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Br J Dis Chest, 2019, 156: 33-46.
38.	Lin CK, Lin YH, Huang TC, et al. VEGF mediates fat embolism-induced acute lung injury via VEGF receptor 2 and the MAPK cascade. Sci Rep, 2019, 9(1): 11713.
39.	Melincovici CS, Bo AB, Mihu C, et al. Vascular endothelial growth factor (VEGF)—Key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018, 59(2): 455-467.
40.	Wewers TM, Mayer AB, Pfleiderer A, et al. Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation. Kidney Int, 2019, 95(5): 1091-1102.
41.	Wallace K, Bean C, Bowles T, et al. Hypertension, anxiety, and blood-brain barrier permeability are increased in postpartum severe preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome rats. Hypertension, 2018, 72(4): 946-954.
42.	Zhang Z, Lu D, Zhang D, et al. Targeted antagonism of vascular endothelial growth factor reduces mortality of mice with acute respiratory distress syndrome. Curr Med Sci, 2020, 40(4): 671-676.
43.	Li X, Shan C, Wu Z, et al. Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1α/VEGF signaling pathway. Inflamm Res, 2020, 69(4): 365-373.
44.	Fan J, Lv H, Li J, et al. Roles of Nrf2/HO‐1 and HIF‐1α/VEGF in lung tissue injury and repair following cerebral ischemia/reperfusion injury. J Cell Physiol, 2019, 234(6): 7695-7707.
45.	Meng L, Wang C, Wang Z, et al. Feixian recipe inhibits pulmonary fibrosis by targeting pulmonary microvascular endothelial cells and VEGF/VEGFR2 signaling pathway. Tradit Med Mod Med, 2018, 1(1): 59-67.
46.	Xu R, Shao Z, Cao Q. MicroRNA-144-3p enhances LPS induced septic acute lung injury in mice through downregulating Caveolin-2. Immunol Lett, 2021, 231: 18-25.
47.	Yuan J, Zhang Y. Sevoflurane reduces inflammatory factor expression, increases viability and inhibits apoptosis of lung cells in acute lung injury by microRNA-34a-3p upregulation and STAT1 downregulation. Chem-Biol Interact, 2020, 322: 109027.
48.	Zhang C, Guo F, Chang M, et al. Exosome-delivered syndecan-1 rescues acute lung injury via a FAK/p190RhoGAP/RhoA/ROCK/NF-κB signaling axis and glycocalyx enhancement. Exp Cell Res, 2019, 384(1): 111596.
49.	Feng G, Sun B, Liu H-X, et al. EphA2 antagonism alleviates LPS-induced acute lung injury via Nrf2/HO-1, TLR4/MyD88 and RhoA/ROCK pathways. Int Immunopharmacol, 2019, 72: 176-185.
50.	Wang H, Sun X, Lu Q, et al. The mitochondrial redistribution of eNOS is involved in lipopolysaccharide induced inflammasome activation during acute lung injury. Redox Biol, 2021, 41: 101878.
51.	Abedi F, Hayes AW, Reiter R, et al. Acute lung injury: The therapeutic role of Rho kinase inhibitors. Pharmacol Res, 2020, 155: 104736.
52.	熊杰, 陈正平, 沈迎念, 等. 抑制Wnt/β-catenin信号通路可减轻脓毒症急性肺损伤. 内科急危重症杂志, 2021, 27(6): 511-516.Xiong J, Chen ZP, Shen YN, et al. Inhibiting Wnt/β-catenin signaling pathway canalleviate acute lung injury in sepsis. J Crit Care Int Med, 2021, 27(6): 511-516.
53.	Lin S, Chen Q, Zhang L, et al. Overexpression of HOXB4 promotes protection of bone marrow mesenchymal stem cells against lipopolysaccharide-induced acute lung injury partially through the activation of Wnt/β-catenin signaling. J Inflamm Res, 2021, 14: 3637-3649.
54.	王博荣, 李鹏程, 刘菲, 等. β-catenin过表达的间充质干细胞对改善海水吸入型肺损伤治疗效果的研究. 中华肺部疾病杂志(电子版), 2018, 11(1): 20-24.Wang BR, Li PC, Liu F, et al. β-catenin overexpl-cssion mesenchymal stem cells improve seawater inhalation induced acute lung injury. Chin J Lung Dis (Electronic Edition), 2018, 11(1): 20-24.

1. Luan G, Pan F, Bu L, et al. Butorphanol promotes macrophage phenotypic transition to inhibit inflammatory lung injury via κ receptors. Front Immunol, 2021, 12: 692286.
2. Arora S, Dev K, Agarwal B, et al. Macrophages: Their role, activation and polarization in pulmonary diseases. Immunobiology, 2018, 223(4): 383-396.
3. Wu G, Zhu Q, Zeng J, et al. Extracellular mitochondrial DNA promote NLRP3 inflammasome activation and induce acute lung injury through TLR9 and NF-κB. J Thorac Dis, 2019, 11(11): 4816-4828.
4. Du ZA, Sun MN, Hu ZS. Saikosaponin a ameliorates LPS-induced acute lung injury in mice. Inflammation, 2018, 41(1): 193-198.
5. Huang X, Liu W, Zhou Y, et al. Dihydroartemisinin attenuates lipopolysaccharide-induced acute lung injury in mice by suppressing NF-κB signaling in an Nrf2-dependent manner. Int J Mol Med, 2019, 44(6): 2213-2222.
6. Hu X, Liu S, Zhu J, et al. Dachengqi decoction alleviates acute lung injury and inhibits inflammatory cytokines production through TLR4/NF‐κB signaling pathway in vivo and in vitro. J Cell Biochem, 2019, 120(6): 8956-8964.
7. Feng T, Zhou L, Gai S, et al. Acacia catechu (L. f. ) Willd and Scutellaria baicalensis Georgi extracts suppress LPS‐induced pro‐inflammatory responses through NF‐кB, MAPK, and PI3K‐Akt signaling pathways in alveolar epithelial type Ⅱ cells. Phytother Res, 2019, 33(12): 3251–3260.
8. Li L, Chen J, Lin L, et al. Quzhou fructus aurantii extract suppresses inflammation via regulation of MAPK, NF-κB, and AMPK signaling pathway. Sci Rep, 2020, 10(1): 1593.
9. Jin M, Feng H, Wang Y, et al. Gentiopicroside ameliorates oxidative stress and lipid accumulation through nuclearfactor erythroid 2-related factor 2 activation. Oxid Med Cell Longev, 2020, 2020: 2940746.
10. Sokolowska M, Quesniaux VFJ, Akdis CA, et al. Acute respiratory barrier disruption by ozone exposure in mice. Front Immunol, 2019, 10: 2169.
11. Li R, Zou X, Huang H, et al. HMGB1/PI3K/Akt/mTOR signaling participates in the pathological process of acute lung injury by regulating the maturation and function of dendritic cells. Front Immunol, 2020, 11: 1104.
12. 吴艳, 张铭, 鲁开智, 等. 腺苷A2b受体激活减轻小鼠肾缺血再灌注致肺损伤. 基础医学与临床, 2019, 39(8): 1102-1107.Wu Y, Zhang M, Lu KZ, et al. Adenosine A2b receptor activation attenuates lung injury induced by renal ischemia-reperfusion in mice. Basic Clin Med, 2019, 39(8): 1102-1107.
13. Huppert LA, Matthay MA. Alveolar fluid clearance in pathologically relevant conditions: In vitro and in vivo models of acute respiratorydistress syndrome. Front Immunol, 2017, 8: 371.
14. Yang J, Li M, Hu X, et al. Protectin DX promotes epithelial injury repair and inhibits fibroproliferation partly via ALX/PI3K signalling pathway. J Cell Mol Med, 2020, 24(23): 14001-14012.
15. Hu X, Xu Q, Wan H, et al. PI3K-Akt-mTOR/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis. Lab Invest, 2020, 100(6): 801-811.
16. Shi J, Yu J, Zhang Y, et al. PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury. Lab Invest, 2019, 99(12): 1795-1809.
17. Yao M, Li F, Xu L, et al. 24-dehydrocholesterol reductase alleviates oxidative damage-induced apoptosis in alveolar epithelial cells via regulating phosphatidylinositol-3-kinase/protein kinase B activation. Bioengineered, 13(1): 155-163.
18. Zhang Z, Zhou Y, Cao J, et al. Rosmarinic acid ameliorates septic-associated mortality and lung injury in mice via GRP78/IRE1α/JNK pathway. J Pharm Pharmacol, 2021, 73(7): 916-921.
19. Zhang Z, Zhang L, Zhou L, et al. Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress. Redox Biol, 2019, 25: 101047.
20. 董超, 李华宇, 区豪杰, 等. 非诺贝特改善脂多糖诱导的急性肺损伤及其机制研究. 天津医药, 2022, 50(1): 59-66.Dong C, Li HY, Qu HJ, et al. Fenofibrate improves acute lung injury induced by lipopolysaccharide. Tianjin Med J, 2022, 50(1): 59-66.
21. Hui Z, Jie H, Fan GH. Expression of DUSP12 reduces lung vascular endothelial cell damage in a murine model of lipopolysaccharide-induced acute lung injury via the apoptosis signal-regulating kinase 1 (ASK1)-Jun N-terminal kinase activation (JNK) pathway. Med Sci Monit, 2021, 27: e930429.
22. Liu S, Su X, Pan P, et al. Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury. Sci Rep, 2016, 6: 37252.
23. Ding J, Zhang Z, Huang W, et al. Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in LPS-induced neutrophil extracellular traps. Microbiol Immunol, 2021, 65(7): 257-264.
24. Yang C, Song C, Liu Y, et al. Re-Du-Ning injection ameliorates LPS-induced lung injury through inhibiting neutrophil extracellular traps formation. Phytomedicine, 2021, 90: 153635.
25. Li D, Pan L, Zhang X, et al. Lower oligomeric form of surfactant protein D in murine acute lung injury induces M1 subtype macrophages through calreticulin/p38 MAPK signaling pathway. Front Immunol, 2021, 12: 687506.
26. Ding Q, Zhu W, Diao Y, et al. Elucidation of the mechanism of action of ginseng against acute lung injury/acute respiratory distress syndrome by a network pharmacology-based strategy. Front Pharmacol, 2020, 11: 611794.
27. Zheng D, Liwinski T, Elinav E. Inflammasome activation and regulation: Toward a better understanding of complex mechanisms. Cell Discovery, 2020, 6(1): 36.
28. Song W, Wei L, Du Y, et al. Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-κB/p38 signaling pathway in high-fat diet/streptozotocin-induced diabetic mice. Int Immunopharmacol, 2018, 63: 227-238.
29. Abd El-Fattah EE, Saber S, Mourad AAE, et al. The dynamic interplay between AMPK/NFκB signaling and NLRP3 is a new therapeutic target in inflammation: Emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury. Biomed Pharmacother, 2022, 147: 112628.
30. He Y, Xu K, Wang Y, et al. AMPK as a potential pharmacological target for alleviating LPS-induced acute lung injury partly via NLRC4 inflammasome pathway inhibition. Exp Gerontol, 2019, 125: 110661.
31. Kosztelnik M, Kurucz A, Papp D, et al. Suppression of AMPK/AAK-2 by NRF2/SKN-1 down-regulates autophagy during prolonged oxidative stress. FASEB J, 2019, 33(2): 2372-2387.
32. Huang XT, Liu W, Zhou Y, et al. Galectin-1 ameliorates lipopolysaccharide-induced acute lung injury via AMPK-Nrf2 pathway in mice. Free Radic Biol Med, 2020, 146: 222-233.
33. Dong W, He B, Qian H, et al. RAB26-dependent autophagy protects adherens junctional integrity in acute lung injury. Autophagy, 2018, 14(10): 1677-1692.
34. Kong X, Lin D, Lu L, et al. Apelin-13-mediated AMPK ameliorates endothelial barrier dysfunction in acute lung injury mice via improvement of mitochondrial function and autophagy. Int Immunopharmacol, 2021, 101(Pt B): 108230.
35. Fu C, Hao S, Xu X, et al. Activation of SIRT1 ameliorates LPS-induced lung injury in mice via decreasing endothelial tight junction permeability. Acta Pharmacol Sin, 2019, 40(5): 630-641.
36. Li X, Jamal M, Guo P, et al. Irisin alleviates pulmonary epithelial barrier dysfunction in sepsis-induced acute lung injury via activation of AMPK/SIRT1 pathways. Biomed Pharmacother, 2019, 118: 109363.
37. Laddha AP, Kulkarni YA. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Br J Dis Chest, 2019, 156: 33-46.
38. Lin CK, Lin YH, Huang TC, et al. VEGF mediates fat embolism-induced acute lung injury via VEGF receptor 2 and the MAPK cascade. Sci Rep, 2019, 9(1): 11713.
39. Melincovici CS, Bo AB, Mihu C, et al. Vascular endothelial growth factor (VEGF)—Key factor in normal and pathological angiogenesis. Rom J Morphol Embryol, 2018, 59(2): 455-467.
40. Wewers TM, Mayer AB, Pfleiderer A, et al. Increased soluble fms-like tyrosine kinase 1 after ischemia reperfusion contributes to adverse clinical outcomes following kidney transplantation. Kidney Int, 2019, 95(5): 1091-1102.
41. Wallace K, Bean C, Bowles T, et al. Hypertension, anxiety, and blood-brain barrier permeability are increased in postpartum severe preeclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome rats. Hypertension, 2018, 72(4): 946-954.
42. Zhang Z, Lu D, Zhang D, et al. Targeted antagonism of vascular endothelial growth factor reduces mortality of mice with acute respiratory distress syndrome. Curr Med Sci, 2020, 40(4): 671-676.
43. Li X, Shan C, Wu Z, et al. Emodin alleviated pulmonary inflammation in rats with LPS-induced acute lung injury through inhibiting the mTOR/HIF-1α/VEGF signaling pathway. Inflamm Res, 2020, 69(4): 365-373.
44. Fan J, Lv H, Li J, et al. Roles of Nrf2/HO‐1 and HIF‐1α/VEGF in lung tissue injury and repair following cerebral ischemia/reperfusion injury. J Cell Physiol, 2019, 234(6): 7695-7707.
45. Meng L, Wang C, Wang Z, et al. Feixian recipe inhibits pulmonary fibrosis by targeting pulmonary microvascular endothelial cells and VEGF/VEGFR2 signaling pathway. Tradit Med Mod Med, 2018, 1(1): 59-67.
46. Xu R, Shao Z, Cao Q. MicroRNA-144-3p enhances LPS induced septic acute lung injury in mice through downregulating Caveolin-2. Immunol Lett, 2021, 231: 18-25.
47. Yuan J, Zhang Y. Sevoflurane reduces inflammatory factor expression, increases viability and inhibits apoptosis of lung cells in acute lung injury by microRNA-34a-3p upregulation and STAT1 downregulation. Chem-Biol Interact, 2020, 322: 109027.
48. Zhang C, Guo F, Chang M, et al. Exosome-delivered syndecan-1 rescues acute lung injury via a FAK/p190RhoGAP/RhoA/ROCK/NF-κB signaling axis and glycocalyx enhancement. Exp Cell Res, 2019, 384(1): 111596.
49. Feng G, Sun B, Liu H-X, et al. EphA2 antagonism alleviates LPS-induced acute lung injury via Nrf2/HO-1, TLR4/MyD88 and RhoA/ROCK pathways. Int Immunopharmacol, 2019, 72: 176-185.
50. Wang H, Sun X, Lu Q, et al. The mitochondrial redistribution of eNOS is involved in lipopolysaccharide induced inflammasome activation during acute lung injury. Redox Biol, 2021, 41: 101878.
51. Abedi F, Hayes AW, Reiter R, et al. Acute lung injury: The therapeutic role of Rho kinase inhibitors. Pharmacol Res, 2020, 155: 104736.
52. 熊杰, 陈正平, 沈迎念, 等. 抑制Wnt/β-catenin信号通路可减轻脓毒症急性肺损伤. 内科急危重症杂志, 2021, 27(6): 511-516.Xiong J, Chen ZP, Shen YN, et al. Inhibiting Wnt/β-catenin signaling pathway canalleviate acute lung injury in sepsis. J Crit Care Int Med, 2021, 27(6): 511-516.
53. Lin S, Chen Q, Zhang L, et al. Overexpression of HOXB4 promotes protection of bone marrow mesenchymal stem cells against lipopolysaccharide-induced acute lung injury partially through the activation of Wnt/β-catenin signaling. J Inflamm Res, 2021, 14: 3637-3649.
54. 王博荣, 李鹏程, 刘菲, 等. β-catenin过表达的间充质干细胞对改善海水吸入型肺损伤治疗效果的研究. 中华肺部疾病杂志(电子版), 2018, 11(1): 20-24.Wang BR, Li PC, Liu F, et al. β-catenin overexpl-cssion mesenchymal stem cells improve seawater inhalation induced acute lung injury. Chin J Lung Dis (Electronic Edition), 2018, 11(1): 20-24.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Research progress on signal pathways in pathogenesis of acute lung injury and the drug intervention

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