The hepatoprotective effect of aspirin on carbon tetrachloride‑induced hepatic fibrosis via inhibition of TGFβ‑1 pathway and pro‑inflammatory cytokines IL‑1β and COX‑2 in rats

Wu,Zhiguo; Wu,Yuchan; Zhong,Weicheng; Zhong,Qingmei; Rao,Shengfang; Yu,Dongshan; Luo,Xiaolu; Qiu,Fang; Song,Zhiying; Jin,Di; Ai,Maoxing; Lan,Yu; Zhang,Gongchang; Song,Shufeng; Xie,Baogang; Sun,Shuilin

doi:10.3892/etm.2023.11931

The hepatoprotective effect of aspirin on carbon tetrachloride‑induced hepatic fibrosis via inhibition of TGFβ‑1 pathway and pro‑inflammatory cytokines IL‑1β and COX‑2 in rats

Authors:
- Zhiguo Wu
- Yuchan Wu
- Weicheng Zhong
- Qingmei Zhong
- Shengfang Rao
- Dongshan Yu
- Xiaolu Luo
- Fang Qiu
- Zhiying Song
- Di Jin
- Maoxing Ai
- Yu Lan
- Gongchang Zhang
- Shufeng Song
- Baogang Xie
- Shuilin Sun
View Affiliations

Affiliations: Department of Infectious Diseases, The Second Affiliated Hospital of Nanchang University, Nanchang University Hospital, Nanchang, Jiangxi 330006, P.R. China, Department of Pathology, The Ninth Hospital of Nanchang, Nanchang, Jiangxi 330006, P.R. China, Department of Nuclear Medicine, Nanchang University Hospital, Nanchang, Jiangxi 330006, P.R. China
Published online on: March 31, 2023 https://doi.org/10.3892/etm.2023.11931
Article Number: 232
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Aspirin decreases liver fibrosis index and inflammation levels. However, the exact mechanism underlying the effects of aspirin are yet to be elucidated. The aim of the study was to investigate the potential protective effects of aspirin on carbon tetrachloride (CCl₄)‑induced hepatic fibrosis in Sprague‑Dawley rats. Rats were divided into four groups, including healthy and CCl₄ control and low‑(aspirin 10 mg/kg + CCl₄) and high‑dose aspirin group (aspirin 300 mg/kg + CCl₄). After 8 weeks treatment, the histopathological examinations of hepatocyte fibrosis in liver and serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL‑1β, transforming growth factor‑β1 (TGF‑β1), hyaluronic acid (HA), laminin (LN) and type IV collagen (IV.C) were determined. Histopathological examination suggested that aspirin decreased CCl₄‑induced hepatic fibrosis and liver inflammation. The high‑dose aspirin group significantly decreased the serum levels of ALT, AST, HA and LN compared with the CCl₄ control group. High‑dose aspirin group significantly decreased the levels of pro‑inflammatory cytokines IL‑1β compared with CCl₄ group. The high‑dose aspirin group significantly inhibited the expression of TGFβ‑1 protein compared with CCl₄ group. Overall, the present study indicated that aspirin exhibited potent protective effects against CCl4‑induced hepatic fibrosis via inhibition of the TGFβ‑1 pathway and pro‑inflammatory cytokine IL‑1β.

View Figures

View References

1	Liu J, Liang W, Jing W and Liu M: Countdown to 2030: Eliminating hepatitis B disease, China. Bull World Health Organ. 97:230–238. 2019.PubMed/NCBI View Article : Google Scholar
2	Mormone E, George J and Nieto N: Molecular pathogenesis of hepatic fibrosis and current therapeutic approaches. Chem Biol Interact. 193:225–231. 2011.PubMed/NCBI View Article : Google Scholar
3	Czaja AJ: Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther. 39:385–406. 2014.PubMed/NCBI View Article : Google Scholar
4	Iredale J: Defining therapeutic targets for liver fibrosis: Exploiting the biology of inflammation and repair. Pharmacol Res. 58:129–136. 2008.PubMed/NCBI View Article : Google Scholar
5	Lee NY and Suk KT: The role of the gut microbiome in liver cirrhosis treatment. Int J Mol Sci. 22(199)2020.PubMed/NCBI View Article : Google Scholar
6	Sun Y, Liu B, Xie J, Jiang X, Xiao B, Hu X and Xiang J: Aspirin attenuates liver fibrosis by suppressing TGF-β1/Smad signaling. Mol Med Rep. 25(181)2022.PubMed/NCBI View Article : Google Scholar
7	Zhu H, Zhao H, Xu S, Zhang Y, Ding Y, Li J, Huang C and Ma T: Sennoside A alleviates inflammatory responses by inhibiting the hypermethylation of SOCS1 in CCl₄-induced liver fibrosis. Pharmacol Res. 174(105926)2021.PubMed/NCBI View Article : Google Scholar
8	Fagone P, Mangano K, Pesce A, Portale TR, Puleo S and Nicoletti F: Emerging therapeutic targets for the treatment of hepatic fibrosis. Drug Discov Today. 21:369–375. 2016.PubMed/NCBI View Article : Google Scholar
9	Adrian JE, Poelstra K, Scherphof GL, Meijer DK, van Loenen-Weemaes AM, Reker-Smit C, Morselt HW, Zwiers P and Kamps JA: Effects of a new bioactive lipid-based drug carrier on cultured hepatic stellate cells and liver fibrosis in bile duct-ligated rats. J Pharmacol Exp Ther. 321:536–543. 2007.PubMed/NCBI View Article : Google Scholar
10	Prud'homme GJ: Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest. 87:1077–1091. 2007.PubMed/NCBI View Article : Google Scholar
11	Song M, Song Z, Barve S, Zhang J, Chen T, Liu M, Arteel GE, Brewer GJ and McClain CJ: Tetrathiomolybdate protects against bile duct ligation-induced cholestatic liver injury and fibrosis. J Pharmacol Exp Ther. 325:409–416. 2008.PubMed/NCBI View Article : Google Scholar
12	Tao Z, Yuan Y, Gu JY, Shi DW, Yao CJ, Tong CY, Shen H, Xue MM, Song Z and Cai YY: Inhibitory effect and mechanism of aspirinin in the treatment of bleomycin-induced pulmonary fibrosis in rats. Fudan Univ J Med Sci. 40:395–399. 2013.
13	Guilherme RF, Xisto DG, Kunkel SL, Freire-de-Lima CG, Rocco PR, Neves JS, Fierro IM, Canetti C and Benjamim CF: Pulmonary antifibrotic mechanisms aspirin-triggered lipoxin A(4) synthetic analog. Am J Respir Cell Mol Biol. 49:1029–1037. 2013.PubMed/NCBI View Article : Google Scholar
14	Jiang ZG, Feldbrügge L, Tapper EB, Popov Y, Ghaziani T, Afdhal N, Robson SC and Mukamal KJ: Aspirin use is associated with lower indices of liver fibrosis among adults in the United States. Aliment Pharmacol Ther. 43:734–743. 2016.PubMed/NCBI View Article : Google Scholar
15	Poujol-Robert A, Boëlle PY, Conti F, Durand F, Duvoux C, Wendum D, Paradis V, Mackiewicz V, Chazouillères O, Corpechot C and Poupon R: Aspirin may reduce liver fibrosis progression: Evidence from a multicenter retrospective study of recurrent hepatitis C after liver transplantation. Clin Res Hepatol Gastroenterol. 38:570–576. 2014.PubMed/NCBI View Article : Google Scholar
16	Yoshida S, Ikenaga N, Liu SB, Peng ZW, Chung J, Sverdlov DY, Miyamoto M, Kim YO, Ogawa S, Arch RH, et al: Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology. 147:1378–1392. 2014.PubMed/NCBI View Article : Google Scholar
17	Gawaz M and Vogel S: Platelets in tissue repair: Control of apoptosis and interactions with regenerative cells. Blood. 122:2550–2554. 2013.PubMed/NCBI View Article : Google Scholar
18	Qing P, Feng T and Chang L: The relationship between platelets and liver fibrosis. J Pract Hepatol. 14:315–317. 2011.
19	Drew DA, Cao Y and Chan AT: Aspirin and colorectal cancer: The promise of precision chemoprevention. Nat Rev Cancer. 16:173–186. 2016.PubMed/NCBI View Article : Google Scholar
20	Hua H, Zhang H, Kong Q, Wang J and Jiang Y: Complex roles of the old drug aspirin in cancer chemoprevention and therapy. Med Res Rev. 39:114–145. 2019.PubMed/NCBI View Article : Google Scholar
21	Sun Y, Zhou J, Wang L, Wu X, Chen Y, Piao H, Lu L, Jiang W, Xu Y, Feng B, et al: New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment. Hepatology. 65:1438–1450. 2017.PubMed/NCBI View Article : Google Scholar
22	Iredale JP: Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 117:539–548. 2007.PubMed/NCBI View Article : Google Scholar
23	Zhang W, Yi Z, Ye CG, Liu CY, Sun SL, Li JM and Xi WN: Interferon α-2a reduces carbon tetrachloride-induced hepatic fibrosis in rats. World Chin J Dig. 19:3207–3211. 2011.
24	lv Y, Wu S, Wang Z and Ye X: Research progress of modeling methods for animal models of liver fibrosis. Guangxi Med J. 42:875–878. 2020.
25	Mu M, Zuo S, Wu RM, Deng KS, Lu S, Zhu JJ, Zou GL, Yang J, Cheng ML and Zhao XK: Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway. Drug Des Devel Ther. 12:4107–4115. 2018.PubMed/NCBI View Article : Google Scholar
26	Li J, Wang Y, Ma M, Jiang S, Zhang X, Zhang Y, Yang X, Xu C, Tian G, Li Q, et al: Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling. EBioMedicine. 40:43–55. 2019.PubMed/NCBI View Article : Google Scholar
27	Chen X, Ying X, Zhang W, Chen Y, Shi C, Hou Y and Zhang Y: The hepatoprotective effect of fraxetin on carbon tetrachloride induced hepatic fibrosis by antioxidative activities in rats. Int Immunopharmacol. 17:543–547. 2013.PubMed/NCBI View Article : Google Scholar
28	Parsons CJ, Takashima M and Rippe RA: Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol. 22 (Suppl 1):S79–S84. 2007.PubMed/NCBI View Article : Google Scholar
29	Oberholzer A, Oberholzer C and Moldawer LL: Cytokine signaling-regulation of the immune response in normal and critically ill states. Crit Care Med. 28 (4 Suppl):N3–N12. 2000.PubMed/NCBI View Article : Google Scholar
30	Wewers MD, Dare HA, Winnard AV, Parker JM and Miller DK: IL-1 beta-converting enzyme (ICE) is present and functional in human alveolar macrophages: Macrophage IL-1 beta release limitation is ICE independent. J Immunol. 159:5964–5972. 1997.PubMed/NCBI
31	Dinarello CA: Biologic basis for interleukin-1 in disease. Blood. 87:2095–2147. 1996.PubMed/NCBI
32	Xu W, Zhang G and Wang H: Detection and significance of IL-1β, mIL-2R and IL-10 in peripheral blood of patients with chronic hepatitis B. Chin J Nosocomiol. 19:742–744. 2009.
33	Zhang H, Zhang J and Deng W: Experimental study of curcumin against hepatic fibrosis in schistosomiasis and its mechanism. Chin Tradit Herbal Drugs. 40:1274–1277. 2009.
34	Mehta P, Ploutz-Snyder R, Nandi J, Rawlins SR, Sanderson SO and Levine RA: Diagnostic accuracy of serum hyaluronic acid, FIBROSpect II, and YKL-40 for discriminating fibrosis stages in chronic hepatitis C. Am J Gastroenterol. 103:928–936. 2008.PubMed/NCBI View Article : Google Scholar
35	Nallagangula KS, Nagaraj SK, Venkataswamy L and Chandrappa M: Liver fibrosis: A compilation on the biomarkers status and their significance during disease progression. Future Sci OA. 4(FSO250)2017.PubMed/NCBI View Article : Google Scholar
36	Wang H, Hui X, Li W, Xu Y, Fan H and Du D: The relationship between serum level of PC III and the liver fibrosis activity. J Mod Lab Med. 21:68–70. 2006.
37	Gressner AM, Weiskirchen R, Breitkopf K and Dooley S: Roles of TGF-beta in hepatic fibrosis. Front Biosci. 7:d793–d807. 2002.PubMed/NCBI View Article : Google Scholar
38	De Minicis S, Seki E, Uchinami H, Kluwe J, Zhang Y, Brenner DA and Schwabe RF: Gene expression profiles during hepatic stellate cell activation in culture and in vivo. Gastroenterology. 132:1937–1946. 2007.PubMed/NCBI View Article : Google Scholar
39	Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA and Schwabe RF: TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med. 13:1324–1332. 2007.PubMed/NCBI View Article : Google Scholar
40	Meng XM, Tang PM, Li J and Lan HY: TGF-β/Smad signaling in renal fibrosis. Front Physiol. 6(82)2015.PubMed/NCBI View Article : Google Scholar
41	Wang Y, Jiang XY, Liu L and Jiang HQ: Phosphatidylinositol 3-kinase/Akt pathway regulates hepatic stellate cell apoptosis. World J Gastroenterol. 14:5186–5191. 2008.PubMed/NCBI View Article : Google Scholar
42	Gäbele E, Reif S, Tsukada S, Bataller R, Yata Y, Morris T, Schrum LW, Brenner DA and Rippe RA: The role of p70S6K in hepatic stellate cell collagen gene expression and cell proliferation. J Biol Chem. 280:13374–13382. 2005.PubMed/NCBI View Article : Google Scholar
43	Yang H, Xuefeng Y, Shandong W and Jianhua X: COX-2 in liver fibrosis. Clin Chim Acta. 506:196–203. 2020.PubMed/NCBI View Article : Google Scholar
44	Wei J, Deng X, Li Y, Li R, Yang Z, Li X, Song S, Shi Y, Duan H and Wu H: PP2 ameliorates renal fibrosis by regulating the NF-κB/COX-2 and PPARγ/UCP2 pathway in diabetic mice. Oxid Med Cell Longev. 2021(7394344)2021.PubMed/NCBI View Article : Google Scholar
45	Xu XF, Fan JW, Xin JQ, Wu N, Gao H, Duan LF, Zou WB, Zhang H and Li ZS: Aspirin ameliorates pancreatic inflammation and fibrosis by inhibiting COX-2 expression in experimental chronic pancreatitis. J Inflamm Res. 15:4737–4749. 2022.PubMed/NCBI View Article : Google Scholar
46	Jiang N, Zhang J, Ping J and Xu L: Salvianolic acid B inhibits autophagy and activation of hepatic stellate cells induced by TGF-β1 by downregulating the MAPK pathway. Front Pharmacol. 13(938856)2022.PubMed/NCBI View Article : Google Scholar
47	Zhao Y, Liu X, Ding C, Zheng Y, Zhu H, Cheng Z, Zhao C and Liu W: Aronia melanocarpa polysaccharide ameliorates liver fibrosis through TGF-β1-mediated the activation of PI3K/AKT pathway and modulating gut microbiota. J Pharmacol Sci. 150:289–300. 2022.PubMed/NCBI View Article : Google Scholar
48	Shang X and Li X: Advances in the experimental research on traditional Chinese medicine against liver fibrosis. J Clin Hepatol. 39:249–259. 2023.