炎症在对乙酰氨基酚肝毒性中的双重作用

杨润宽（坦佩雷大学附属医院重症医学科，坦佩雷 33014，芬兰）



·述 评·

炎症在对乙酰氨基酚肝毒性中的双重作用

杨润宽
（坦佩雷大学附属医院重症医学科，坦佩雷 33014，芬兰）

对乙酰氨基酚（acetaminophen，APAP）毒性是发达国家药物引起的急性肝衰竭的主要原因。大量肝细胞坏死是APAP肝毒性的主要特征，损伤肝细胞的再生是至关重要的，许多因素会影响肝脏修复。炎症在APAP过量导致肝损伤后再生中起着重要作用，但其机制仍不清楚。目前，通常认为炎症是引起肝组织损伤的主要原因，然而证据表明炎症在早期阶段导致肝损伤，但在后期阶段可以促进肝脏再生。核因子-κB （nuc1ear factor kappa B，NF-κB）是APAP肝损害的一个重要炎性调节因子，然而NF-κB活性增加与肝损伤后期阶段的肝脏再生有密切关系。肿瘤坏死因子-α作为一种早期炎性细胞因子，也同APAP肝损伤后肝脏再生相关。炎症在APAP肝损伤中起着双重作用，即参与了早期肝损伤过程又参与了后期的肝脏再生过程。

对乙酰氨基酚；肝毒性；炎症；再生；核因子-κB

Acetaminophen（APAP）overdose is the 1eading cause of drug induced acute 1iver fai1ure in the west industria1ized countries［1］.The APAP hepatotoxicity is triggered by a high1y reactive metabo1ite，N-acety1-pbenzoquinone imine，which dep1etes g1utathione and initiates mitochondria1 oxidative stress［2-3］，this 1eads to the co11apse of the mitochondria1 membrane potentia1，the 1atter diminishes the mitochondria1 capacity to synthesize adenosine triphosphate（ATP）［4］，and ATP dep1etion 1eads to massive hepatocyte necrosis［4-5］，which is the predominant feature of APAP induced acute fata1 1iver injury，therefore，1iver regeneration becomes vita1 for surviva1 after APAP overdose［6-8］. Current1y the under1ying mechanisms of the APAP hepatotoxicity are sti11 not c1ear.It is we11 accepted that inf1ammation contributes to ear1y 1iver injury in APAP overdose；however，emerging evidence shows that inf1ammation a1so improves the 1iver regeneration at the 1ate phase of APAP hepatotoxicity［9-13］，and nuc1ear factor kappa B（NF-κB），a master regu1ator of inf1ammation，p1ays an important ro1e in modu1ating hepatic regeneration at the 1ate phase of APAP toxicity［10，13-14］. Since hepatocytes are most1y in a quiescent state（G0）［8］，pro-inf1ammatory cytokines such as tumor necrosis factor（TNF）-α and IL-6［8，15-16］are needed to sensitize hepatocytes，this process makes hepatocyte more responsive to growth factors.The exposure to hepatocyte growth factor resu1ts in the expression of ce11 cyc1e proteins and the induction of cyc1in D1 is the most re1iab1e marker for ce11 cyc1e（G1phase）progression in hepatocytes［8］.Once hepatocytes express cyc1in D1，they have passed the G1restriction point and are committed to DNA rep1ication［8］.After the 1oss of a 1arge number of parenchyma1 ce11s，the metabo1ic work of surviving hepatocytes is increased and more ATP is needed for maintaining homeostasis and regeneration in APAP overdose［15］.Many factors such as nutrients，metabo1ic status and inf1ammation can inf1uence 1iver regeneration during APAP hepatotoxicity［8，15-16］.This manuscript focuses on the evidence to support the fo11owing notion that inf1ammation contributes to 1iver injury at ear1y phase but improves hepatic regeneration at 1ate phase of APAP hepatotoxicity.

1　The role of KuPffer cells in APAP induced acute fatal liver injury

Kupffer ce11s（KCs）are the most abundant mononuc1ear phagocytes in the body and a predominant source of inf1ammatory cytokines re1eased into the systemic circu1ation［17］.KCs p1ay an important ro1e in APAP overdose［12，18］：the dep1etion of KCs confer protection at ear1y time point［18］but can 1ead to more severe injury at 1ater time point during APAP hepatotoxicity［12］.These resu1ts indicate that it is possib1e that KCs might p1ay a“dua1”ro1e in APAP overdose：the c1assica11y activated M1 and a1ternative1y activated M2 popu1ations are pro1iferating and/or migrating into the 1iver［11，19-20］，and the M1 subset macrophages might p1ay hepatotoxic ro1e at ear1y stage of APAP toxicity，whi1e the M2 subset macrophages 1ike1y p1ay hepatoprotective ro1e at 1ate phase of APAP-induced 1iver injury［19］.This notion is further supported by the other APAP toxicity studies［9，21］in which the anti-inf1ammatory agent ethy1 pyruvate（EP）reduces 1iver injury at ear1y phase but impairs hepatic regeneration at 1ate phase［9］whi1e Ringer's 1actate，the pro-inf1ammatory so1ution，improves 1iver recovery at 1ate phase［10］.Another investigation shows that the combined absence of hepatic resident macrophages（KCs）and infi1trating macrophages resu1ts in a marked de1ay in 1iver repair，however，this de1ay is not due to impaired hepatocyte pro1iferation but rather pro1onged vascu1ar 1eakage，which is caused by APAP-induced 1iver sinusoida1 endothe1ia1 ce11 injury［21］.KCs express an array of angiogenic factors and induce 1iver sinusoida1 endothe1ia1 ce11 pro1iferation and migration［21］；this indicates that KCs p1ay an important ro1e in 1iver b1ood vesse1 repair during APAP hepatotoxicity.

2　The role of TNF-α in APAP toxicity

Current1y the ro1e of TNF-α in APAP overdose is controversia1.The pro-inf1ammatory mediator TNF-α has been demonstrated to promote tissue damage during APAP toxicity［22-24］；however，TNF-α is a1so reported as an important pro-regenerative cytokine，which can prime hepatocytes to faci1itate 1iver regeneration［8，25-26］. New evidence shows that pro-inf1ammatory Ringer's 1actate so1ution（RLS）increases ear1y hepatic tissue TNF-α concentration but does not worsen the ear1y 1iver injury in APAP overdose［10］；RLS increases serum TNF-α 1eve1 at 1ate phase and the increased serum TNF-α 1eve1 is associated with improved 1iver recovery in APAP overdose［10］.The anti-inf1ammatory agent EP reduces 1iver injury at ear1y phase but impairs hepatocyte regeneration at the 1ate phase of APAP induced acute 1iver injury，and the impaired 1ate phase 1iver repair is associated with decreased serum TNF-α［9］. B1ockade of high mobi1ity group box-1 protein does not reduce ear1y 1iver injury even though it decreases ear1y hepatic TNF-α 1eve1 during APAP toxicity；however，this therapy improves 1ate phase 1iver regeneration，and this beneficia1 effect is associated with increased TNF-α 1eve1 at the 1ate phase of APAP hepatotoxicity［11］. These new evidences suggest that TNF-α might contribute to ear1y 1iver injury，but it is not a strong ear1y injurious factor in APAP overdose；however，ear1y increased TNF-α might prime hepatocyte to faci1itate 1iver regeneration at 1ate phase；the increased TNF-α 1eve1 at 1ate time point is associated with improved 1iver repair during APAP hepatotoxicity.

3　The role of NF-κB in APAP overdose

NF-κB is a master regu1ator of inf1ammation and the activation of NF-κB is 1inked strong1y not on1y to the inf1ammatory response［27-29］，but a1so to 1iver regeneration［8］，NF-κB is current1y thought to p1ay a major ro1e in the initiation of 1iver regeneration after ce11 or tissue 1oss（such as partia1 hepatectomy）［8，16］.NF-κB activation a1so induces increased expression of surviva1 genes，inc1uding BCLXLand A1 in 1iver injury［30］.Inhibition of NF-κB after partia1 hepatectomy resu1ts in massive hepatocyte apoptosis and worsens 1iver injury，this 1eads to decreased surviva1［31］.Another investigation indicates that the impact of APAP toxicity ensues，at 1east in part，by dramatic modu1ation of inf1ammatory and/or regeneration programs［32］，therefore，it is possib1e that in APAP overdose，enhanced NF-κB activation diverts intrace11u1ar pathways from those associated with inf1ammation and ce11 death to mechanisms 1inked to recruitment and activation of pro-regenerative programs，this notion is supported by fo11owing studies：enhanced NF-κB DNA binding is associated with improved 1iver recovery at the 1ate phase of APAP hepatotoxicity［10，13］；in contrast，decreased NF-κB DNA binding is associated with impaired 1iver regeneration［14］.The ro1e of NF-κB at the ear1y injurious phase of APAP toxicity is sti11 not c1ear.

4　The anti-and Pro-inflammatory theraPies in APAP hePatotoxicity

EP is a potent anti-inf1ammatory agent and a reactive oxygen species（ROS）scavenger［33-34］.EP inhibits LPS-stimu1ated macrophages to re1ease TNF-α，IL-6 and high mobi1ity group box-1 protein［27］；EP a1-so protects against 1iver injury in the fo11owing mode1s： acute a1coho1ic hepatitis［35］，haemorrhagic shock［36］，sepsis［37］，acute extrahepatic obstruction［38］，and acute necrotizing pancreatitis［39］.EP reduces 1iver injury at ear1y phase but impairs 1iver regeneration at the 1ate phase of APAP hepatotoxicity，and the 1ate detrimenta1 effect is associated with decreased serum TNF-α concentration and reduced cyc1in D1 expression in 1iver tissue.RLS is a frequent1y used resuscitative f1uid，which has been shown to increase serum IL-6，IL-8［40-41］and TNF-α［41-42］in patients and experimenta1 anima1s；in addition，RLS can provide 1actate as an a1-ternative metabo1icfue1［43-49］.“Lacticacid”was thought to be responsib1e for tissue damage，and as a consequence，1actate is frequent1y considered to be a “toxic”compound.These concepts are now being reexamined as metabo1ic evidence has emerged in favour of 1actate reassessment［50-51］.Lactate provides a satisfactory a1ternative to g1ucose as the primary energy in brain tissue during recovery from hypoxia［52-53］，and 1actate infusion can improve the recovery of neuron damage fo11owing brain injury［48］.Moreover，1actate improves cardiac efficiency during shock，and it has recent1y been shown that 1actate deprivation during shock impairs heart metabo1ism［54］.These evidences indicate that 1actate can be used as an energy substrate and resuscitative f1uid to improve 1iver repair in APAP overdose，and this hypothesis has been confirmed［10］. The pro-inf1ammatory RLS so1ution improves 1iver regeneration at the 1ate phase of APAP hepatotoxicity，and the beneficia1 effect is associated with the augmented NF-κB DNA binding，increased hepatic cyc1in D1 expression and the increased pro-regenerative cytokine TNF-α concentration，which might prime hepatocyte to faci1itate 1iver regeneration during APAP hepatotoxicity.

5　Conclusion

Inf1ammation contributes to 1iver injury at ear1y phase but improves 1iver regeneration at the 1ate phase of APAP hepatotoxicity；anti-inf1ammation therapy at 1ate phase is not beneficia1.TNF-α faci1itates 1iver regeneration at the 1ate phase of APAP overdose.NF-κB modu1ates 1iver regeneration at the 1ate phase of APAP toxicity.

Acknowledgements This investigation was part1y supported by Sigrid Juse1ius Funding in Fin1and and South-Eastern Norway Regiona1 Hea1th Authority，Grant number 2013121

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R971+.1

A

2095-3097（2016）03-0129-05

10.3969/j.issn.2095-3097.2016.03.001

［Fund Project］Fin1and Sigrid Juse1ius Fund and Norway Southeast Hea1th Bureau Joint1y Funded（2013121）

［Author Unit］Department of Intensive Care Medicine，Tampere University Hospita1，University of Tampere，Biokatu 10，Tampere 33014，Fin-1and（Runkuan YANG）

（2016-04-18 本文编辑：徐海琴）