Resveratrol protects against asthma‑induced airway inflammation and remodeling by inhibiting the HMGB1/TLR4/NF‑κB pathway

Jiang,Huanhuan; Duan,Junyan; Xu,Kaihong; Zhang,Wenbo

doi:10.3892/etm.2019.7594

Resveratrol protects against asthma‑induced airway inflammation and remodeling by inhibiting the HMGB1/TLR4/NF‑κB pathway

Authors:
- Huanhuan Jiang
- Junyan Duan
- Kaihong Xu
- Wenbo Zhang
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Affiliations: Department of Pediatrics, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
Published online on: May 20, 2019 https://doi.org/10.3892/etm.2019.7594
Pages: 459-466
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to explore the protective role of resveratrol (RES) in asthma‑induced airway inflammation and remodeling, as well as its underlying mechanism. An asthma rat model was induced by ovalbumin (OVA) treatment. Rats were randomly assigned into sham, asthma, 10 µmol/l RES and 50 µmol/l RES groups. The amount of inflammatory cells in rat bronchoalveolar lavage fluid (BALF) was detected. Pathological lesions in lung tissues were accessed by hematoxylin and eosin (H&E), and Masson's trichrome staining. Levels of inflammatory factors in lung homogenate were detected via ELISA. The blood serum of asthmatic and healthy children was also collected for analysis. Reverse transcription‑quantitative polymerase chain reaction was performed to detect high mobility group box 1 (HMGB1), Τoll‑like receptor 4 (TLR4), myeloid differentiation primary response gene 88 (MyD88) and NF‑κB expression in asthmatic and healthy children, as well as rats of the different groups. H&E staining demonstrated that multiple inflammatory cell infiltration into the rat airway epithelium of the asthma group occurred whilst the 50 µmol/l RES group displayed alleviated pathological lesions. Masson staining indicated that there was an increased airway collagen deposition area in the asthma and 10 µmol/l RES groups compared with the 50 µmol/l RES group. The number of inflammatory cells in BALF extracted from rats of the asthma and 10 µmol/l RES groups was higher compared with the 50 µmol/l RES group. Treatment with 50 µmol/l RES significantly decreased the thicknesses of the airway wall and smooth muscle. ELISA results illustrated that interleukin (IL)‑1, IL‑10 and tumor necrosis factor‑α (TNF‑α) levels were elevated, whereas IL‑12 level was reduced in lung tissues of the asthma and 10 µmol/l RES groups whilst the 50 µmol/l RES group demonstrated the opposite trend. HMGB1, TLR4, MyD88 and NF‑κB mRNA levels were remarkably elevated in rats of the asthma and 10 µmol/l RES groups compared with the 50 µmol/l RES group. Serum levels of IL‑1, IL‑10 and TNF‑α were elevated, whereas IL‑12 was reduced in asthmatic children compared with healthy children. The present results demonstrated that a large dose of RES alleviated asthma‑induced airway inflammation and airway remodeling by inhibiting the release of inflammatory cytokines via the HMGB1/TLR4/NF‑κB pathway.

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1	Guilbert TW, Mauger DT and Lemanske RF Jr: Childhood asthma-predictive phenotype. J Allergy Clin Immunol Pract. 2:664–670. 2014. View Article : Google Scholar : PubMed/NCBI
2	Pinfield J, Gaskin K, Bentley J and Rouse J: Recognition and management of asthma in children and young people. Nurs Stand. 30:50–58. 2015. View Article : Google Scholar : PubMed/NCBI
3	Us'Ka VR: Role of psychological factors in the etiology of asthma in children. Lik Sprava. 148–150. 2015.(In Ukrainian). PubMed/NCBI
4	Croisant S: Epidemiology of asthma: Prevalence and burden of disease. Adv Exp Med Biol. 795:17–29. 2014. View Article : Google Scholar : PubMed/NCBI
5	Raedler D and Schaub B: Immune mechanisms and development of childhood asthma. Lancet Respir Med. 2:647–656. 2014. View Article : Google Scholar : PubMed/NCBI
6	Rosenberg SL, Miller GE, Brehm JM and Celedon JC: Stress and asthma: Novel insights on genetic, epigenetic and immunologic mechanisms. J Allergy Clin Immunol. 134:1009–1015. 2014. View Article : Google Scholar : PubMed/NCBI
7	Khan DA: Allergic rhinitis and asthma: Epidemiology and common pathophysiology. Allergy Asthma Proc. 35:357–361. 2014. View Article : Google Scholar : PubMed/NCBI
8	Yang Q, Liu X, Yao Z, Mao S, Wei Q and Chang Y: Penehyclidine hydrochloride inhibits the release of high-mobility group box 1 in lipopolysaccharide-activated RAW264.7 cells and cecal ligation and puncture-induced septic mice. J Surg Res. 186:310–317. 2014. View Article : Google Scholar : PubMed/NCBI
9	Musumeci D, Roviello GN and Montesarchio D: An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther. 141:347–357. 2014. View Article : Google Scholar : PubMed/NCBI
10	Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, Arnold B, Bianchi ME, Manfredi AA and Rovere-Querini P: Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol. 174:7506–7515. 2005. View Article : Google Scholar : PubMed/NCBI
11	Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A and Abraham E: Involvement of Τoll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 279:7370–7377. 2004. View Article : Google Scholar : PubMed/NCBI
12	Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J, Lu B, Chavan S, Rosas-Ballina M, Al-Abed Y, et al: A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA. 107:11942–11947. 2010. View Article : Google Scholar : PubMed/NCBI
13	Andersson U, Wang H, Palmblad K, Aveberger AC, Bloom O, Erlandsson-Harris H, Janson A, Kokkola R, Zhang M, Yang H and Tracey KJ: High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 192:565–570. 2000. View Article : Google Scholar : PubMed/NCBI
14	Park JS, Arcaroli J, Yum HK, Yang H, Wang H, Yang KY, Choe KH, Strassheim D, Pitts TM, Tracey KJ and Abraham E: Activation of gene expression in human neutrophils by high mobility group box 1 protein. Am J Physiol Cell Physiol. 284:C870–C879. 2003. View Article : Google Scholar : PubMed/NCBI
15	Wang J, He F, Chen L, Li Q, Jin S, Zheng H, Lin J, Zhang H, Ma S, Mei J and Yu J: Resveratrol inhibits pulmonary fibrosis by regulating miR-21 through MAPK/AP-1 pathways. Biomed Pharmacother. 105:37–44. 2018. View Article : Google Scholar : PubMed/NCBI
16	Wang XL, Li T, Li JH, Miao SY and Xiao XZ: The effects of resveratrol on inflammation and oxidative stress in a rat model of chronic obstructive pulmonary disease. Molecules. 22:E15292017. View Article : Google Scholar : PubMed/NCBI
17	Yang DL, Zhang HG, Xu YL, Gao YH, Yang XJ, Hao XQ and Li XH: Resveratrol inhibits right ventricular hypertrophy induced by monocrotaline in rats. Clin Exp Pharmacol Physiol. 37:150–155. 2010. View Article : Google Scholar : PubMed/NCBI
18	Oh YC, Kang OH, Choi JG, Chae HS, Lee YS, Brice OO, Jung HJ, Hong SH, Lee YM and Kwon DY: Anti-inflammatory effect of resveratrol by inhibition of IL-8 production in LPS-induced THP-1 cells. Am J Chin Med. 37:1203–1214. 2009. View Article : Google Scholar : PubMed/NCBI
19	Tan Y and Lim LH: Trans-Resveratrol, an extract of red wine, inhibits human eosinophil activation and degranulation. Br J Pharmacol. 155:995–1004. 2008. View Article : Google Scholar : PubMed/NCBI
20	Colitti M and Stefanon B: Different anti-adipogenic effects of bio-compounds on primary visceral pre-adipocytes and adipocytes. EXCLI J. 15:362–377. 2016.PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Ebenezer AJ, Prasad K, Rajan S and Thangam EB: Silencing of H4R inhibits the production of IL-1β through SAPK/JNK signaling in human mast cells. J Recept Signal Transduct Res. 38:204–212. 2018. View Article : Google Scholar : PubMed/NCBI
23	Zhang Y, Feng Y, Li L, Ye X, Wang J, Wang Q, Li P, Li N, Zheng X, Gao X, et al: Immunization with an adenovirus-vectored TB vaccine containing Ag85A-Mtb32 effectively alleviates allergic asthma. J Mol Med (Berl). 96:249–263. 2018. View Article : Google Scholar : PubMed/NCBI
24	Lin CL, Hsiao G, Wang CC and Lee YL: Imperatorin exerts antiallergic effects in Th2-mediated allergic asthma via induction of IL-10-producing regulatory T cells by modulating the function of dendritic cells. Pharmacol Res. 110:111–121. 2016. View Article : Google Scholar : PubMed/NCBI
25	Abraham E, Arcaroli J, Carmody A, Wang H and Tracey KJ: HMG-1 as a mediator of acute lung inflammation. J Immunol. 165:2950–2954. 2000. View Article : Google Scholar : PubMed/NCBI
26	Kim JY, Park JS, Strassheim D, Douglas I, Diaz del Valle F, Asehnoune K, Mitra S, Kwak SH, Yamada S, Maruyama I, et al: HMGB1 contributes to the development of acute lung injury after hemorrhage. Am J Physiol Lung Cell Mol Physiol. 288:L958–L965. 2005. View Article : Google Scholar : PubMed/NCBI
27	Bauer EM, Shapiro R, Zheng H, Ahmad F, Ishizawar D, Comhair SA, Erzurum SC, Billiar TR and Bauer PM: High mobility group box 1 contributes to the pathogenesis of experimental pulmonary hypertension via activation of Toll-like receptor 4. Mol Med. 18:1509–1518. 2013. View Article : Google Scholar : PubMed/NCBI
28	Dumitriu IE, Bianchi ME, Bacci M, Manfredi AA and Rovere-Querini P: The secretion of HMGB1 is required for the migration of maturing dendritic cells. J Leukoc Biol. 81:84–91. 2007. View Article : Google Scholar : PubMed/NCBI
29	Messmer D, Yang H, Telusma G, Knoll F, Li J, Messmer B, Tracey KJ and Chiorazzi N: High mobility group box protein 1: An endogenous signal for dendritic cell maturation and Th1 polarization. J Immunol. 173:307–313. 2004. View Article : Google Scholar : PubMed/NCBI
30	Lotfi R, Herzog GI, DeMarco RA, Beer-Stolz D, Lee JJ, Rubartelli A, Schrezenmeier H and Lotze MT: Eosinophils oxidize damage-associated molecular pattern molecules derived from stressed cells. J Immunol. 183:5023–5031. 2009. View Article : Google Scholar : PubMed/NCBI
31	Liang Y, Hou C, Kong J, Wen H, Zheng X, Wu L, Huang H and Chen Y: HMGB1 binding to receptor for advanced glycation end products enhances inflammatory responses of human bronchial epithelial cells by activating p38 MAPK and ERK1/2. Mol Cell Biochem. 405:63–71. 2015. View Article : Google Scholar : PubMed/NCBI
32	Granucci F, Zanoni I, Feau S and Ricciardi-Castagnoli P: Dendritic cell regulation of immune responses: A new role for interleukin 2 at the intersection of innate and adaptive immunity. EMBO J. 22:2546–2551. 2003. View Article : Google Scholar : PubMed/NCBI
33	Kawai T and Akira S: The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat Immunol. 11:373–384. 2010. View Article : Google Scholar : PubMed/NCBI
34	MacLeod H and Wetzler LM: T cell activation by TLRs: A role for TLRs in the adaptive immune response. Sci STKE. 2007:pe482007. View Article : Google Scholar : PubMed/NCBI
35	Lee KY, Ho SC, Lin HC, Lin SM, Liu CY, Huang CD, Wang CH, Chung KF and Kuo HP: Neutrophil-derived elastase induces TGF-beta1 secretion in human airway smooth muscle via NF-kappaB pathway. Am J Respir Cell Mol Biol. 35:407–414. 2006. View Article : Google Scholar : PubMed/NCBI
36	Mazarati A, Maroso M, Iori V, Vezzani A and Carli M: High-mobility group box-1 impairs memory in mice through both Τoll-like receptor 4 and receptor for advanced Glycation end products. Exp Neurol. 232:143–148. 2011. View Article : Google Scholar : PubMed/NCBI
37	Yu M, Wang H, Ding A, Golenbock DT, Latz E, Czura CJ, Fenton MJ, Tracey KJ and Yang H: HMGB1 signals through Τoll-like receptor (TLR) 4 and TLR2. Shock. 26:174–179. 2006. View Article : Google Scholar : PubMed/NCBI
38	Yadav M, Jain S, Bhardwaj A, Nagpal R, Puniya M, Tomar R, Singh V, Parkash O, Prasad GB, Marotta F and Yadav H: Biological and medicinal properties of grapes and their bioactive constituents: An update. J Med Food. 12:473–484. 2009. View Article : Google Scholar : PubMed/NCBI
39	Eo SH, Cho H and Kim SJ: Resveratrol inhibits nitric oxide-induced apoptosis via the NF-kappa B pathway in rabbit articular chondrocytes. Biomol Ther (Seoul). 21:364–370. 2013. View Article : Google Scholar : PubMed/NCBI
40	Csaki C, Keshishzadeh N, Fischer K and Shakibaei M: Regulation of inflammation signalling by resveratrol in human chondrocytes in vitro. Biochem Pharmacol. 75:677–687. 2008. View Article : Google Scholar : PubMed/NCBI
41	Shakibaei M, John T, Seifarth C and Mobasheri A: Resveratrol inhibits IL-1 beta-induced stimulation of caspase-3 and cleavage of PARP in human articular chondrocytes in vitro. Ann NY Acad Sci. 1095:554–563. 2007. View Article : Google Scholar : PubMed/NCBI
42	Elmali N, Esenkaya I, Harma A, Ertem K, Turkoz Y and Mizrak B: Effect of resveratrol in experimental osteoarthritis in rabbits. Inflamm Res. 54:158–162. 2005. View Article : Google Scholar : PubMed/NCBI
43	Im HJ, Li X, Chen D, Yan D, Kim J, Ellman MB, Stein GS, Cole B, Kc R, Cs-Szabo G and van Wijnen AJ: Biological effects of the plant-derived polyphenol resveratrol in human articular cartilage and chondrosarcoma cells. J Cell Physiol. 227:3488–3497. 2012. View Article : Google Scholar : PubMed/NCBI
44	Manna SK, Mukhopadhyay A and Aggarwal BB: Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1 and apoptosis: Potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol. 164:6509–6519. 2000. View Article : Google Scholar : PubMed/NCBI
45	Estrov Z, Shishodia S, Faderl S, Harris D, Van Q, Kantarjian HM, Talpaz M and Aggarwal BB: Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood. 102:987–995. 2003. View Article : Google Scholar : PubMed/NCBI
46	Zhang C, Lin G, Wan W, Li X, Zeng B, Yang B and Huang C: Resveratrol, a polyphenol phytoalexin, protects cardiomyocytes against anoxia/reoxygenation injury via the TLR4/NF-κB signaling pathway. Int J Mol Med. 29:557–563. 2012. View Article : Google Scholar : PubMed/NCBI