Emodin ameliorates acute pancreatitis‑induced lung injury by suppressing NLRP3 inflammasome‑mediated neutrophil recruitment

Jiang,Nan; Li,Zhaoxia; Luo,Yalan; Jiang,Liu; Zhang,Guixin; Yang,Qi; Chen,Hailong

doi:10.3892/etm.2021.10289

August-2021 Volume 22 Issue 2

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August-2021 Volume 22 Issue 2

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Article Open Access

Emodin ameliorates acute pancreatitis‑induced lung injury by suppressing NLRP3 inflammasome‑mediated neutrophil recruitment

Authors:
- Nan Jiang
- Zhaoxia Li
- Yalan Luo
- Liu Jiang
- Guixin Zhang
- Qi Yang
- Hailong Chen
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China

Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 857
|
Published online on: June 9, 2021

https://doi.org/10.3892/etm.2021.10289
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Abstract

Severe acute pancreatitis (SAP) activates the systemic inflammatory response and is potentially lethal. The aim of the present study was to determine the effects of emodin on acute lung injury (ALI) in rats with SAP and investigate the role of the Nod‑like receptor protein 3 (NLRP3) inflammasome and its association with neutrophil recruitment. Sodium taurocholate (5.0%) was used to establish the SAP model. All animals were randomly assigned into four groups: Sham, SAP, emodin and dexamethasone (positive control drug) groups (n=10 mice per group). Histopathology observation of pancreatic and lung tissues was detected by hematoxylin and eosin staining. The levels of serum amylase, IL‑1β and IL‑18 were measured by ELISA. Single‑cell suspensions were obtained from enzymatically digested lung tissues, followed by flow cytometric analysis for apoptosis. In addition, the expression levels of NLRP3 inflammasome‑associated and apoptosis‑associated proteins in lung tissues were measured by western blotting. Moreover, lymphocyte antigen 6 complex locus G6D⁺ (Ly6G⁺) cell recruitment was detected using immunohistochemical analysis. The results revealed that emodin markedly improved pancreatic histological injury and decreased the levels of serum amylase, IL‑1β and IL‑18. Pulmonary edema and apoptosis were significantly alleviated by emodin. Additionally, the protein expression levels of intercellular adhesion molecule 1, NLRP3, apoptosis‑associated speck‑like protein containing a CARD and cleaved caspase‑1 were downregulated following emodin treatment. Moreover, emodin inhibited Ly6G⁺ cell recruitment in lung tissues. The present study demonstrated that emodin may offer protection against ALI induced by SAP via inhibiting and suppressing NLRP3 inflammasome‑mediated neutrophil recruitment and may be a novel therapeutic strategy for the clinical treatment of ALI.

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1	Donnelly PE and Winch DE: Acute pancreatitis. N Engl J Med. 376(597)2017.PubMed/NCBI View Article : Google Scholar
2	Goldacre MJ and Roberts SE: Hospital admission for acute pancreatitis in an English population, 1963-98: Database study of incidence and mortality. BMJ. 328:1466–1469. 2004.PubMed/NCBI View Article : Google Scholar
3	Grupp K, Bonk S, Poppe A, Wodack K, Reeh M, Gocht A, Mann O, Izbicki JR and Bachmann K: Cholecystokinin-8 treatment reduces acinar necrosis and edema of pigs with induced pancreatitis. Asian J Surg. 43:272–277. 2020.PubMed/NCBI View Article : Google Scholar
4	Granger J and Remick D: Acute pancreatitis: Models, markers, and mediators. Shock. 24 (Suppl 1):S45–S51. 2005.PubMed/NCBI View Article : Google Scholar
5	Pastor CM, Matthay MA and Frossard JL: Pancreatitis-associated acute lung injury: New insights. Chest. 124:2341–2351. 2003.PubMed/NCBI View Article : Google Scholar
6	Li Z, Xia X, Zhang S, Zhang A, Bo W and Zhou R: Up-regulation of Toll-like receptor 4 was suppressed by emodin and baicalin in the setting of acute pancreatitis. Biomed Pharmacother. 63:120–128. 2009.PubMed/NCBI View Article : Google Scholar
7	Gukovskaya AS, Gukovsky I, Algül H and Habtezion A: Autophagy, inflammation, and immune dysfunction in the pathogenesis of pancreatitis. Gastroenterology. 153:1212–1226. 2017.PubMed/NCBI View Article : Google Scholar
8	Fu Q, Zhai Z, Wang Y, Xu L, Jia P, Xia P, Liu C, Zhang X, Qin T and Zhang H: NLRP3 deficiency alleviates severe acute pancreatitis and pancreatitis-associated lung injury in a mouse model. Biomed Res Int. 2018(1294951)2018.PubMed/NCBI View Article : Google Scholar
9	Yang M, Chen XM, Du XG, Cao FF, Vijaya Luxmi S and Shen Q: Continuous blood purification ameliorates endothelial hyperpermeability in SAP patients with MODS by regulating tight junction proteins via ROCK. Int J Artif Organs. 36:700–709. 2013.PubMed/NCBI View Article : Google Scholar
10	Tian X, Sun H, Casbon AJ, Lim E, Francis KP, Hellman J and Prakash A: NLRP3 inflammasome mediates dormant neutrophil recruitment following sterile lung injury and protects against subsequent bacterial pneumonia in mice. Front Immunol. 8(1337)2017.PubMed/NCBI View Article : Google Scholar
11	Hoque R, Farooq A, Ghani A, Gorelick F and Mehal WZ: Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology. 146:1763–1774. 2014.PubMed/NCBI View Article : Google Scholar
12	Dolinay T, Kim YS, Howrylak J, Hunninghake GM, An CH, Fredenburgh L, Massaro AF, Rogers A, Gazourian L, Nakahira K, et al: Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med. 185:1225–1234. 2012.PubMed/NCBI View Article : Google Scholar
13	Johnson GB, Brunn GJ and Platt JL: Cutting edge: An endogenous pathway to systemic inflammatory response syndrome (SIRS)-like reactions through Toll-like receptor 4. J Immunol. 172:20–24. 2004.PubMed/NCBI View Article : Google Scholar
14	Hietaranta A, Mustonen H, Puolakkainen P, Haapiainen R and Kemppainen E: Proinflammatory effects of pancreatic elastase are mediated through TLR4 and NF-kappaB. Biochem Biophys Res Commun. 323:192–196. 2004.PubMed/NCBI View Article : Google Scholar
15	Li Y, Zhou ZG, Zhang J, Chen YD, Li HG, Gao HK, Wang R and Hu TZ: Microcirculatory detection of Toll-like receptor 4 in rat pancreas and intestine. Clin Hemorheol Microcirc. 34:213–219. 2006.PubMed/NCBI
16	Watanabe T, Kudo M and Strober W: Immunopathogenesis of pancreatitis. Mucosal Immunol. 10:283–298. 2017.PubMed/NCBI View Article : Google Scholar
17	Zhou R, Yazdi AS, Menu P and Tschopp J: A role for mitochondria in NLRP3 inflammasome activation. Nature. 469:221–225. 2011.PubMed/NCBI View Article : Google Scholar
18	Cai X, Chen J, Xu H, Liu S, Jiang QX, Halfmann R and Chen ZJ: Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell. 156:1207–1222. 2014.PubMed/NCBI View Article : Google Scholar
19	Jin HZ, Yang XJ, Zhao KL, Mei FC, Zhou Y, You YD and Wang WX: Apocynin alleviates lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Int Immunopharmacol. 75(105821)2019.PubMed/NCBI View Article : Google Scholar
20	Baroja-Mazo A, Martín-Sánchez F, Gomez AI, Martínez CM, Amores-Iniesta J, Compan V, Barberà-Cremades M, Yagüe J, Ruiz-Ortiz E, Antón J, et al: The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol. 15:738–748. 2014.PubMed/NCBI View Article : Google Scholar
21	Ma Q, Chen S, Hu Q, Feng H, Zhang JH and Tang J: NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol. 75:209–219. 2014.PubMed/NCBI View Article : Google Scholar
22	Chou RC, Kim ND, Sadik CD, Seung E, Lan Y, Byrne MH, Haribabu B, Iwakura Y and Luster AD: Lipid-cytokine-chemokine cascade drives neutrophil recruitment in a murine model of inflammatory arthritis. Immunity. 33:266–278. 2010.PubMed/NCBI View Article : Google Scholar
23	Mayadas TN, Cullere X and Lowell CA: The multifaceted functions of neutrophils. Annu Rev Pathol. 9:181–218. 2014.PubMed/NCBI View Article : Google Scholar
24	Kuo YC, Tsai WJ, Meng HC, Chen WP, Yang LY and Lin CY: Immune reponses in human mesangial cells regulated by emodin from Polygonum hypoleucum Ohwi. Life Sci. 68:1271–1286. 2001.PubMed/NCBI View Article : Google Scholar
25	Xu C, Zhang J, Liu J, Li Z, Liu Z, Luo Y, Xu Q, Wang M, Zhang G, Wang F and Chen H: Proteomic analysis reveals the protective effects of emodin on severe acute pancreatitis induced lung injury by inhibiting neutrophil proteases activity. J Proteomics. 220(103760)2020.PubMed/NCBI View Article : Google Scholar
26	Xu J, Huang B, Wang Y, Tong C, Xie P, Fan R and Gao Z: Emodin ameliorates acute lung injury induced by severe acute pancreatitis through the up-regulated expressions of AQP1 and AQP5 in lung. Clin Exp Pharmacol Physiol. 43:1071–1079. 2016.PubMed/NCBI View Article : Google Scholar
27	Wu Y, Tu X, Lin G, Xia H, Huang H, Wan J, Cheng Z, Liu M, Chen G, Zhang H, et al: Emodin-mediated protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic myocardium. Life Sci. 81:1332–1338. 2007.PubMed/NCBI View Article : Google Scholar
28	Ding Y, Zhao L, Mei H, Zhang SL, Huang ZH, Duan YY and Ye P: Exploration of Emodin to treat alpha-naphthylisothiocyanate-induced cholestatic hepatitis via anti-inflammatory pathway. Eur J Pharmacol. 590:377–386. 2008.PubMed/NCBI View Article : Google Scholar
29	Gao Z, Sui J, Fan R, Qu W, Dong X and Sun D: Emodin protects against acute pancreatitis-associated lung injury by inhibiting nlpr3 inflammasome activation via Nrf2/HO-1 signaling. Drug Des Devel Ther. 14:1971–1982. 2020.PubMed/NCBI View Article : Google Scholar
30	Xu C, Luo Y, Ntim M, Quan W, Li Z, Xu Q, Jiang L, Zhang J, Shang D, Li L, et al: Effect of emodin on long non-coding RNA-mRNA networks in rats with severe acute pancreatitis-induced acute lung injury. J Cell Mol Med. 25:1851–1866. 2021.PubMed/NCBI View Article : Google Scholar
31	Guan M, Ma H, Fan X, Chen X, Miao M and Wu H: Dexamethasone alleviate allergic airway inflammation in mice by inhibiting the activation of NLRP3 inflammasome. Int Immunopharmacol. 78(106017)2020.PubMed/NCBI View Article : Google Scholar
32	Yoshida K, Okamura H, Hiroshima Y, Abe K, Kido JI, Shinohara Y and Ozaki K: PKR induces the expression of NLRP3 by regulating the NF-κB pathway in Porphyromonas gingivalis-infected osteoblasts. Exp Cell Res. 354:57–64. 2017.PubMed/NCBI View Article : Google Scholar
33	Zhang JW, Zhang GX, Chen HL, Liu GL, Owusu L, Wang YX, Wang GY and Xu CM: Therapeutic effect of Qingyi decoction in severe acute pancreatitis-induced intestinal barrier injury. World J Gastroenterol. 21:3537–3546. 2015.PubMed/NCBI View Article : Google Scholar
34	Schmidt J, Rattner DW, Lewandrowski K, Compton CC, Mandavilli U, Knoefel WT and Warshaw AL: A better model of acute pancreatitis for evaluating therapy. Ann Surg. 215:44–56. 1992.PubMed/NCBI View Article : Google Scholar
35	Wu Q, Gui P, Yao S and Xiang H: Expression of integrin alpha v beta 6 in rats with ventilator-induced lung injury and the attenuating effect of synthesized peptide S247. Med Sci Monit. 14:BR41–BR48. 2008.PubMed/NCBI
36	Martinon F, Burns K and Tschopp J: The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 10:417–426. 2002.PubMed/NCBI View Article : Google Scholar
37	Khomtchouk KM, Joseph LI, Khomtchouk BB, Kouhi A, Massa S, Xia A, Koliesnik I, Pletzer D, Bollyky PL and Santa Maria PL: Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media. NPJ Biofilms Microbiomes. 7(31)2021.PubMed/NCBI View Article : Google Scholar
38	Xu Y, Lu B, Zhang N, Liang Y, Gao Y, Ye X and Liu W: Neutrophil extracellular traps are not produced in pediatric patients with one-lung ventilation: A prospective, single-center, observational study. Transl Pediatr. 9:775–783. 2020.PubMed/NCBI View Article : Google Scholar
39	Browne GW and Pitchumoni CS: Pathophysiology of pulmonary complications of acute pancreatitis. World J Gastroenterol. 12:7087–7096. 2006.PubMed/NCBI View Article : Google Scholar
40	Gao Z, Xu J, Sun D, Zhang R, Liang R, Wang L and Fan R: Traditional Chinese medicine, Qing Ying Tang, ameliorates the severity of acute lung injury induced by severe acute pancreatitis in rats via the upregulation of aquaporin-1. Exp Ther Med. 8:1819–1824. 2014.PubMed/NCBI View Article : Google Scholar
41	Zhang H, Neuhöfer P, Song L, Rabe B, Lesina M, Kurkowski MU, Treiber M, Wartmann T, Regnér S, Thorlacius H, et al: IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J Clin Invest. 123:1019–1031. 2013.PubMed/NCBI View Article : Google Scholar
42	Janowitz T, Kleeman S and Vonderheide RH: Reconsidering dexamethasone for antiemesis when combining chemotherapy and immunotherapy. Oncologist. 26:269–273. 2021.PubMed/NCBI View Article : Google Scholar
43	Pontes-Quero GM, Benito-Garzón L, Pérez Cano J, Aguilar MR and Vázquez-Lasa B: Modulation of inflammatory mediators by polymeric nanoparticles loaded with anti-inflammatory drugs. Pharmaceutics. 13(290)2021.PubMed/NCBI View Article : Google Scholar
44	Sugiyama Y, Kato S, Abe M, Mitsufuji S and Takeuchi K: Different effects of dexamethasone and the nitric oxide synthase inhibitor L-NAME on caerulein-induced rat acute pancreatitis, depending on the severity. Inflammopharmacology. 13:291–301. 2005.PubMed/NCBI View Article : Google Scholar
45	Buzatto AZ, Malkawi A, Sabi EM, Mujamammi AH, Li L and Abdel Rahman AM: Tissue lipidomic alterations induced by prolonged dexamethasone treatment. J Proteome Res. 20:1558–1570. 2021.PubMed/NCBI View Article : Google Scholar
46	Grommes J and Soehnlein O: Contribution of neutrophils to acute lung injury. Mol Med. 17:293–307. 2011.PubMed/NCBI View Article : Google Scholar
47	Faller S, Hausler F, Goeft A, von Itter MA, Gyllenram V, Hoetzel A and Spassov SG: Hydrogen sulfide limits neutrophil transmigration, inflammation, and oxidative burst in lipopolysaccharide-induced acute lung injury. Sci Rep. 8(14676)2018.PubMed/NCBI View Article : Google Scholar
48	Amaral FA, Costa VV, Tavares LD, Sachs D, Coelho FM, Fagundes CT, Soriani FM, Silveira TN, Cunha LD, Zamboni DS, et al: NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B(4) in a murine model of gout. Arthritis Rheum. 64:474–484. 2012.PubMed/NCBI View Article : Google Scholar
49	Inoue Y, Shirasuna K, Kimura H, Usui F, Kawashima A, Karasawa T, Tago K, Dezaki K, Nishimura S, Sagara J, et al: NLRP3 regulates neutrophil functions and contributes to hepatic ischemia-reperfusion injury independently of inflammasomes. J Immunol. 192:4342–4351. 2014.PubMed/NCBI View Article : Google Scholar
50	Fann DY, Lee SY, Manzanero S, Chunduri P, Sobey CG and Arumugam TV: Pathogenesis of acute stroke and the role of inflammasomes. Ageing Res Rev. 12:941–966. 2013.PubMed/NCBI View Article : Google Scholar
51	Garlanda C, Dinarello CA and Mantovani A: The interleukin-1 family: Back to the future. Immunity. 39:1003–1018. 2013.PubMed/NCBI View Article : Google Scholar
52	Crother TR, Porritt RA, Dagvadorj J, Tumurkhuu G, Slepenkin AV, Peterson EM, Chen S, Shimada K and Arditi M: Autophagy limits inflammasome during chlamydia pneumoniae infection. Front Immunol. 10(754)2019.PubMed/NCBI View Article : Google Scholar
53	Sun Y, Abbondante S, Karmakar M, de Jesus Carrion S, Che C, Hise AG and Pearlman E: Neutrophil caspase-11 is required for cleavage of caspase-1 and secretion of IL-1β in aspergillus fumigatus infection. J Immunol. 201:2767–2775. 2018.PubMed/NCBI View Article : Google Scholar
54	McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA and Kubes P: Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 330:362–366. 2010.PubMed/NCBI View Article : Google Scholar
55	Zhou W, McCollum MO, Levine BA and Olson MS: Role of platelet-activating factor in pancreatitis-associated acute lung injury in the rat. Am J Pathol. 140:971–979. 1992.PubMed/NCBI