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Fibroblast growth factor 9 attenuates sepsis-induced fulminant hepatitis in mice

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Abstract

Sepsis-induced fulminant hepatitis (FH) is a fatal syndrome that has a worse prognosis in clinical practice. Hence, seeking effective agents for sepsis-induced FH treatment is urgently needed. Fibroblast growth factors (FGFs) are vital for tissue homeostasis and damage repair in various organs including the liver. Our study aims to investigate the protective effects and potential mechanisms of FGF9 on lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced FH in mice. We found that pre-treatment with FGF9 exhibited remarkable hepaprotective effects on liver damage caused by LPS/D-Gal, as manifested by the concomitant decrease in mortality and serum aminotransferase activities, and the attenuation of hepatocellular apoptosis and hepatic histopathological abnormalities in LPS/D-Gal-intoxicated mice. We further found that FGF9 alleviated the infiltration of neutrophils into the liver, and decreased the serum levels of pro‐inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in LPS/D-Gal-challenged mice. These effects can be explained at least in part by the inhibition of NF-κB signaling pathway. Meanwhile, FGF9 enhanced the antioxidative defense system in mice livers by upregulating the expression of NRF-2-related antioxidative enzymes, including glutamate-cysteine ligase catalytic subunit (GCLC), NAD(P)H: quinone oxidoreductase 1 (NQO-1), and heme oxygenase-1 (HO-1). These data indicate that FGF9 represents a promising therapeutic drug for ameliorating sepsis-induced FH via its anti-apoptotic and anti-inflammatory capacities.

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References

  • Ambade A, Catalano D, Lim A, Mandrekar P (2012) Inhibition of heat shock protein (molecular weight 90 kDa) attenuates proinflammatory cytokines and prevents lipopolysaccharide-induced liver injury in mice. Hepatology 55(5):1585–1595

    Article  CAS  Google Scholar 

  • Antoine M, Wirz W, Tag CG, Gressner AM, Marvituna M, Wycislo M, Hellerbrand C, Kiefer P (2007) Expression and function of fibroblast growth factor (FGF) 9 in hepatic stellate cells and its role in toxic liver injury. Biochem Bioph Res Co 361(2):335–341

    Article  CAS  Google Scholar 

  • Bajt ML, Vonderfecht SL, Jaeschke H (2001) Differential protection with inhibitors of caspase-8 and caspase-3 in murine models of tumor necrosis factor and Fas receptor-mediated hepatocellular apoptosis. Toxicol Appl Pharma 175(3):243–252

    Article  CAS  Google Scholar 

  • Bunchorntavakul C, Reddy KR (2017) Acute liver failure. Clin Liver Dis 21(4):769–792

    Article  Google Scholar 

  • Fyfe B, Zaldana F, Liu C (2018) The pathology of acute liver failure. Clin Liver Dis 22(2):257–268

    Article  Google Scholar 

  • Galanos C, Freudenberg MA, Reutter W (1979) Galactosamine-induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA 76(11):5939–5943

    Article  CAS  Google Scholar 

  • Ge M, Yao WF, Yuan DD, Zhou SL, Chen X, Zhang YH, Li HB, Xia ZY, Hei ZQ (2017) Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury. Cell Death Dis 8(6):e2841

    Article  CAS  Google Scholar 

  • Gong XB, Yang Y, Huang LG, Zhang QY, Wan RZ, Zhang P, Zhang BS (2017) Antioxidation, anti-inflammation and anti-apoptosis by paeonol in LPS/D-GalN-induced acute liver failure in mice. Int Immunopharmacol 46:124–132

    Article  CAS  Google Scholar 

  • Hu J, Zhu ZJ, Ying HL, Yao J, Ma HB, Li L, Zhao YF (2021) Oleoylethanolamide protects against acute liver injury by regulating Nrf-2/HO-1 and NLRP3 pathways in mice. Front Pharmacol 11:2338

    Google Scholar 

  • Jeffers M, McDonald WF, Chillakuru RA, Yang MJ, Nakase H, Deegler LL, Sylander ED, Rittman B, Bendele A, Sartor RB, Lichenstein HS (2002) A novel human fibroblast growth factor treats experimental intestinal inflammation. Gastroenterology 123(41):1151–1162

    Article  CAS  Google Scholar 

  • Jing ZT, Liu W, Xue CR, Wu SX, Chen WN, Lin XJ, Lin X (2019) AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates D-Gal/LPS-induced liver injury. Am J Physiol-Gastr L 316(3):G387-396

    CAS  Google Scholar 

  • Li A, Zhang JY, Xiao X, Wang SS, Wan JB, Chai YS, Li P, Wang YT (2018a) Hepatorenal protective effects of medicinal herbs in An-Gong-Niu-Huang Wan (AGNH) against cinnabar-and realgar-induced oxidative stress and inflammatory damage in mice. Food Chem Toxicol 119:445–456

    Article  CAS  Google Scholar 

  • Li M, Wang S, Li X, Jiang LL, Wang XJ, Kou RR, Wang Q, Xu L, Zhao N, Xie KQ (2018b) Diallyl sulfide protects against lipopolysaccharide/D-galactosamine-induced acute liver injury by inhibiting oxidative stress, inflammation and apoptosis in mice. Food Chem Toxicol 120:500–509

    Article  CAS  Google Scholar 

  • Lv HM, Fan XY, Wang LD, Feng HH, Ci XX (2018) Daphnetin alleviates lipopolysaccharide/D-galactosamine-induced acute liver failure via the inhibition of NLRP3, MAPK and NF-κB, and the induction of autophagy. Int J Biol Macromol 119:240–248

    Article  CAS  Google Scholar 

  • Lv HM, An BY, Yu QL, Cao Y, Liu Y, Li SZ (2020) The hepatoprotective effect of myricetin against lipopolysaccharide and D-galactosamine-induced fulminant hepatitis. Int J Biol Macromol 155:1092–1104

    Article  CAS  Google Scholar 

  • Mayoral R, Mollá B, Flores JM, Boscá L, Casado M, Martín-Sanz P (2008) Constitutive expression of cyclo-oxygenase 2 transgene in hepatocytes protects against liver injury. Biochem J 416(3):337–346

    Article  CAS  Google Scholar 

  • Miyauchi T, Uchida Y, Kadono K, Hirao H, Kawasoe J, Watanabe T, Ueda T, Okajima H, Terajima H, Uemoto S (2019) Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury. Proc Natl Acad Sci USA 116(27):13533–13542

    Article  CAS  Google Scholar 

  • Seitz T, Freese K, Dietrich P, Thasler WE, Bosserhoff A, Hellerbrand C (2020) Fibroblast growth factor 9 is expressed by activated hepatic stellate cells and promotes progression of hepatocellular carcinoma. Sci Rep 10(1):1–9

    Article  Google Scholar 

  • Wang S, Lin HP, Zhao TT, Huang SS, Fernig DG, Xu N, Wu FF, Zhou M, Jiang C, Tian HS (2017) Expression and purification of an FGF9 fusion protein in E. coli, and the effects of the FGF9 subfamily on human hepatocellular carcinoma cell proliferation and migration. Appl Microbiol Biot 101(21):7823–7835

    Article  CAS  Google Scholar 

  • Wang W, Wu LL, Li Q, Zhang Z, Xu LB, Lin CX, Gao L, Zhao KL, Liang F, Zhang Q, Zhou M, Jiang WZ (2018) Madecassoside prevents acute liver failure in LPS/D-GalN-induced mice by inhibiting p38/NF-κB and activating Nrf2/HO-1 signaling. Biomed Pharmacother 103:1137–1145

    Article  CAS  Google Scholar 

  • Xia XM, Su CY, Fu JL, Zhang P, Jiang XJ, Xu DM, Hu LH, Song EQ, Song Y (2014) Role of α-lipoic acid in LPS/ D-GalN induced fulminant hepatic failure in mice: studies on oxidative stress, inflammation and apoptosis. Int Immunopharmacol 22(2):293–302

    Article  CAS  Google Scholar 

  • Zhao N, Guo FF, Xie KQ, Zeng T (2018) Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci 75(17):3143–3157

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by the Zhejiang Provincial Natural Science Foundation of China (LY19H160029), the National Natural Science Foundation of China (82174058), the Guangdong Basic and Applied Basic Research Foundation (2021A1515012229), the Chongqing Natural Science Foundation (cstc2019jcyj-msxmX0045), and the TCM project of Chongqing Municipal Health and Family Planning Commission (ZY201702122).

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Author notes

  1. Ao Li and Xue-Mei Li have contributed equally to this work.

Authors and Affiliations

  1. Clinical Research Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China

    Ao Li, Xue-Mei Li & Xiao Xiao

  2. College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China

    Xue-Mei Li & Xiao Xiao

  3. Department of Respiratory Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China

    Chu-Ge Song & Wei-Min Yao

  4. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Hai-Shan Tian

Authors
  1. Ao Li
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  2. Xue-Mei Li
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  3. Chu-Ge Song
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  4. Xiao Xiao
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  5. Wei-Min Yao
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Contributions

Ao Li and Xue-Mei Li carried out the experiments and should be considered co-first authors. Ao Li and Xiao Xiao drafted the manuscript. Chu-Ge Song conducted data analysis. Hai-Shan Tian prepared the recombinant FGF9 protein. Ao Li, Wei-Min Yao, and Hai-Shan Tian conceived and designed this project.

Corresponding authors

Correspondence to Ao Li, Wei-Min Yao or Hai-Shan Tian.

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The authors declare no competing financial interest.

Ethical approval

All procedures involving animals were approved by the Animal Care and Use Committee of Chongqing University of Technology, and were conducted in accordance with the NIH guidelines for the care and use of laboratory animals (8th Edition, 2011).

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All experimental data and analysis are included in this article.

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Handling editor: M. S. Palma.

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Li, A., Li, XM., Song, CG. et al. Fibroblast growth factor 9 attenuates sepsis-induced fulminant hepatitis in mice. Amino Acids 54, 1069–1081 (2022). https://doi.org/10.1007/s00726-022-03143-7

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  • DOI: https://doi.org/10.1007/s00726-022-03143-7

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