肝再生在对乙酰氨基酚诱导的肝损伤修复中的作用
DOI: 10.12449/JCH240929
利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:莫胤康负责设计论文框架,起草论文;范子豪、莫胤康负责论文修改;任锋负责拟定写作思路,指导撰写文章并最后定稿。
Role of liver regeneration in the repair of liver injury induced by N-acetyl-p-aminophenol
-
摘要: 肝再生在对乙酰氨基酚(APAP)诱导的肝损伤后恢复中有着至关重要的作用。APAP过量服用后,通常是肝损伤程度越大,再生的程度就越大,从而导致肝损伤的消退和大多数情况下的自发恢复。然而,严重APAP过量会导致肝再生受损和无法控制的肝损伤,导致无法恢复,甚至死亡。在APAP肝损伤后,肝脏中细胞之间的相互作用对再生反应非常重要。肝再生由多种增殖信号通路共同调控,这些通路涉及激酶、核受体、转录因子、转录共激活因子。严重的APAP过量后会抑制增殖信号通路的激活,导致细胞周期停滞和肝再生受损。虽然肝再生在APAP肝损伤后的修复过程中发挥关键作用,但目前其发挥作用的潜在机制尚不明确。本文就已有的相关研究对肝再生在APAP诱导的肝损伤中的作用进行综述, 为进一步的基础研究提供参考。
-
关键词:
- 化学性与药物性肝损伤 /
- 对乙酰氨基酚 /
- 信号传导 /
- 修复
Abstract: Liver regeneration plays a crucial role in the recovery after liver injury induced by N-acetyl-p-aminophenol (APAP). After APAP overdose, the degree of regeneration increases with the extent of liver injury, leading to the resolution of liver injury and spontaneous recovery in most cases. However, severe APAP overdose can impair liver regeneration and result in uncontrolled liver injury, even failure to recover or death in severe cases. Following APAP-induced liver injury, interactions between cells in the liver are essential for regenerative response. Liver regeneration is jointly regulated by multiple proliferative signaling pathways, involving various kinases, nuclear receptors, transcription factors, and coactivators. Severe APAP overdose can inhibit the activation of proliferative signaling pathways, thereby causing cell cycle arrest and impairing liver regeneration. Although liver regeneration plays a critical role in the repair of APAP-induced liver injury, the underlying mechanisms remain unclear. This article reviews the research advances in the role of liver regeneration in APAP-induced liver injury, in order to provide a reference for further basic research in this area.-
Key words:
- Chemical and Drug Induced Liver Injury /
- Acetaminophen /
- Signal Transduction /
- Repair
-
[1] XU Y, XIA Y, LIU QH, et al. Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites[J]. J Pharm Anal, 2023, 13( 12): 1548- 1561. DOI: 10.1016/j.jpha.2023.08.004. [2] JAESCHKE H, RAMACHANDRAN A. Acetaminophen hepatotoxicity: Paradigm for understanding mechanisms of drug-induced liver injury[J]. Annu Rev Pathol, 2024, 19: 453- 478. DOI: 10.1146/annurev-pathmechdis-051122-094016. [3] RAMACHANDRAN A, AKAKPO JY, CURRY SC, et al. Clinically relevant therapeutic approaches against acetaminophen hepatotoxicity and acute liver failure[J]. Biochem Pharmacol, 2024: 116056. DOI: 10.1016/j.bcp.2024.116056. [4] APTE U, SINGH S, ZENG G, et al. Beta-catenin activation promotes liver regeneration after acetaminophen-induced injury[J]. Am J Pathol, 2009, 175( 3): 1056- 1065. DOI: 10.2353/ajpath.2009.080976. [5] NGUYEN NT, UMBAUGH DS, SANCHEZ-GUERRERO G, et al. Kupffer cells regulate liver recovery through induction of chemokine receptor CXCR2 on hepatocytes after acetaminophen overdose in mice[J]. Arch Toxicol, 2022, 96( 1): 305- 320. DOI: 10.1007/s00204-021-03183-0. [6] DONAHOWER B, MCCULLOUGH SS, KURTEN R, et al. Vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 291( 1): G102- G109. DOI: 10.1152/ajpgi.00575.2005. [7] BHUSHAN B, WALESKY C, MANLEY M, et al. Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model[J]. Am J Pathol, 2014, 184( 11): 3013- 3025. DOI: 10.1016/j.ajpath.2014.07.019. [8] LUO TT, YANG SZ, ZHAO TM, et al. Hepatocyte DDX3X protects against drug-induced acute liver injury via controlling stress granule formation and oxidative stress[J]. Cell Death Dis, 2023, 14( 7): 400. DOI: 10.1038/s41419-023-05913-x. [9] MANGIPUDY RS, CHANDA S, MEHENDALE HM. Tissue repair response as a function of dose in thioacetamide hepatotoxicity[J]. Environ Health Perspect, 1995, 103( 3): 260- 267. DOI: 10.1289/ehp.95103260. [10] MICHALOPOULOS GK, BHUSHAN B. Liver regeneration: Biological and pathological mechanisms and implications[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 1): 40- 55. DOI: 10.1038/s41575-020-0342-4. [11] KOMPOSCH K, SIBILIA M. EGFR signaling in liver diseases[J]. Int J Mol Sci, 2015, 17( 1): 30. DOI: 10.3390/ijms17010030. [12] BHUSHAN B, KORAL K, STOOPS JW, et al. Hepatic deletion of MET aggravates acetaminophen hepatotoxicity and impairs liver regeneration in mice[J]. FASEB J, 2020, 34( S1): 1. DOI: 10.1096/fasebj.2020.34.s1.05879. [13] WEI MJ, GU XN, LI H, et al. EGR1 is crucial for the chlorogenic acid-provided promotion on liver regeneration and repair after APAP-induced liver injury[J]. Cell Biol Toxicol, 2023, 39( 6): 2685- 2707. DOI: 10.1007/s10565-023-09795-9. [14] KOTULKAR M, PAINE-CABRERA D, ABERNATHY S, et al. Role of HNF4alpha-cMyc interaction in liver regeneration and recovery after acetaminophen-induced acute liver injury[J]. Hepatology, 2023, 78( 4): 1106- 1117. DOI: 10.1097/HEP.0000000000000367. [15] BHUSHAN B, CHAVAN H, BORUDE P, et al. Dual role of epidermal growth factor receptor in liver injury and regeneration after acetaminophen overdose in mice[J]. Toxicol Sci, 2017, 155( 2): 363- 378. DOI: 10.1093/toxsci/kfw213. [16] ZHANG ZZ, YAO TT, ZHAO N, et al. Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway[J]. Int J Biol Sci, 2022, 18( 6): 2317- 2328. DOI: 10.7150/ijbs.69609. [17] SCHMIDT-ARRAS D, ROSE-JOHN S. IL-6 pathway in the liver: From physiopathology to therapy[J]. J Hepatol, 2016, 64( 6): 1403- 1415. DOI: 10.1016/j.jhep.2016.02.004. [18] CHIU H, GARDNER CR, DAMBACH DM, et al. Role of tumor necrosis factor receptor 1(p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice[J]. Toxicol Appl Pharmacol, 2003, 193( 2): 218- 227. DOI: 10.1016/j.taap.2003.07.003. [19] BHUSHAN B, POUDEL S, MANLEY MW Jr, et al. Inhibition of glycogen synthase kinase 3 accelerated liver regeneration after acetaminophen-induced hepatotoxicity in mice[J]. Am J Pathol, 2017, 187( 3): 543- 552. DOI: 10.1016/j.ajpath.2016.11.014. [20] POUDEL S, CABRERA DP, BHUSHAN B, et al. Hepatocyte-specific deletion of yes-associated protein improves recovery from acetaminophen-induced acute liver injury[J]. Toxicol Sci, 2021, 184( 2): 276- 285. DOI: 10.1093/toxsci/kfab115. [21] XU M, WANG HC, WANG JX, et al. mTORC2 signaling is necessary for timely liver regeneration after partial hepatectomy[J]. Am J Pathol, 2020, 190( 4): 817- 829. DOI: 10.1016/j.ajpath.2019.12.010. [22] MIREAULT M, PRINVILLE V, OHLUND L, et al. Semi-targeted profiling of bile acids by high-resolution mass spectrometry in a rat model of drug-induced liver injury[J]. Int J Mol Sci, 2023, 24( 3): 2489. DOI: 10.3390/ijms24032489. [23] EVERTON E, DEL RIO-MORENO M, VILLACORTA-MARTIN C, et al. Growth hormone accelerates recovery from acetaminophen-induced murine liver injury[J]. BioRxiv, 2023: 2023. 04. 17. 537197. DOI: 10.1101/2023.04.17.537197. [24] BORUDE P, BHUSHAN B, APTE U. DNA damage response regulates initiation of liver regeneration following acetaminophen overdose[J]. Gene Expr, 2018, 18( 2): 115- 123. DOI: 10.3727/105221618X15205260749346. [25] BIRD TG, MÜLLER M, BOULTER L, et al. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence[J]. Sci Transl Med, 2018, 10( 454): eaan1230. DOI: 10.1126/scitranslmed.aan1230. [26] XU PF, XI Y, WANG PC, et al. Inhibition of p53 sulfoconjugation prevents oxidative hepatotoxicity and acute liver failure[J]. Gastroenterology, 2022, 162( 4): 1226- 1241. DOI: 10.1053/j.gastro.2021.12.260. [27] VISWANATHAN P, SHARMA Y, GUPTA P, et al. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration[J]. Cell Prolif, 2018, 51( 3): e12445. DOI: 10.1111/cpr.12445. [28] MARTUCCI N, MICHALOPOULOS GK, MARS WM. Integrin linked kinase(ILK) and its role in liver pathobiology[J]. Gene Expr, 2021, 20( 3): 201- 207. DOI: 10.3727/105221621X16113475275710. [29] BHUSHAN B, EDWARDS G, DESAI A, et al. Liver-specific deletion of integrin-linked kinase in mice attenuates hepatotoxicity and improves liver regeneration after acetaminophen overdose[J]. Gene Expr, 2016, 17( 1): 35- 45. DOI: 10.3727/105221616X691578. [30] HU CX, ZHAO LF, WU ZW, et al. Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury[J]. Stem Cell Res Ther, 2020, 11( 1): 88. DOI: 10.1186/s13287-020-01596-9. [31] CHANG WJ, SONG LJ, CHANG XJ, et al. Early activated hepatic stellate cell-derived paracrine molecules modulate acute liver injury and regeneration[J]. Lab Invest, 2017, 97( 3): 318- 328. DOI: 10.1038/labinvest.2016.130. [32] SHEN KT, CHANG WJ, GAO XD, et al. Depletion of activated hepatic stellate cell correlates with severe liver damage and abnormal liver regeneration in acetaminophen-induced liver injury[J]. Acta Biochim Biophys Sin, 2011, 43( 4): 307- 315. DOI: 10.1093/abbs/gmr005. [33] DONAHOWER BC, MCCULLOUGH SS, HENNINGS L, et al. Human recombinant vascular endothelial growth factor reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity[J]. J Pharmacol Exp Ther, 2010, 334( 1): 33- 43. DOI: 10.1124/jpet.109.163840. [34] KATO T, ITO Y, HOSONO K, et al. Vascular endothelial growth factor receptor-1 signaling promotes liver repair through restoration of liver microvasculature after acetaminophen hepatotoxicity[J]. Toxicol Sci, 2011, 120( 1): 218- 229. DOI: 10.1093/toxsci/kfq366. [35] STARKEY LEWIS P, CAMPANA L, ALEKSIEVA N, et al. Alternatively activated macrophages promote resolution of necrosis following acute liver injury[J]. J Hepatol, 2020, 73( 2): 349- 360. DOI: 10.1016/j.jhep.2020.02.031. [36] BEN-MOSHE S, VEG T, MANCO R, et al. The spatiotemporal program of zonal liver regeneration following acute injury[J]. Cell Stem Cell, 2022, 29( 6): 973- 989. e 10. DOI: 10.1016/j.stem.2022.04.008.