Atorvastatin has a protective effect in a mouse model of bronchial asthma through regulating tissue transglutaminase and triggering receptor expressed on myeloid cells‑1 expression

Liu,Ming‑Wei; Liu,Rong; Wu,Hai‑Ying; Chen,Mei; Dong,Min‑Na; Huang,Yun‑Qiao; Zhang,Chun‑Hai; Wang,Yin‑Zhong; Xia,Jing; Shi,Yang; Xie,Feng‑Mei; Luo,Hua; Zhao,Xin‑Yuan; Wei,Wei; Su,Mei‑Xian

doi:10.3892/etm.2017.4576

Atorvastatin has a protective effect in a mouse model of bronchial asthma through regulating tissue transglutaminase and triggering receptor expressed on myeloid cells‑1 expression

Authors:
- Ming‑Wei Liu
- Rong Liu
- Hai‑Ying Wu
- Mei Chen
- Min‑Na Dong
- Yun‑Qiao Huang
- Chun‑Hai Zhang
- Yin‑Zhong Wang
- Jing Xia
- Yang Shi
- Feng‑Mei Xie
- Hua Luo
- Xin‑Yuan Zhao
- Wei Wei
- Mei‑Xian Su
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Affiliations: Department of Emergency, The First Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650032, P.R. China, Department of Respiratory Medicine, The Yan'An Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650051, P.R. China, Department of Gastroenterology, The Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650106, P.R. China, Department of Emergency, The Second Hospital Affiliated to Kunming Medical University, Kunming, Yunnan 650106, P.R. China
Published online on: June 9, 2017 https://doi.org/10.3892/etm.2017.4576
Pages: 917-930
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. Statin drugs have improved respiratory health and their therapeutic potential in asthma has been tested in clinical trials. However, the mechanism of action of statins in this context has remained elusive. The present study hypothesized that atorvastatin treatment of ovalbumin‑exposed mice attenuates early features of airway remodeling via a mevalonate‑dependent mechanism. BALB/c mice were sensitized with ovalbumin and atorvastatin was delivered via oral gavage prior to each ovalbumin exposure. Reverse transcription‑semi‑quantitative polymerase chain reaction (RT‑semi‑qPCR), ELISA and western blot analysis were used to assess the expression of a number of relevant genes, including tissue transglutaminase (tTG), triggering receptor expressed on myeloid cells (TREM)‑1, nuclear factor erythroid 2‑related factor (Nrf) 2, hypoxia‑inducible factor (HIF)‑1α, transforming growth factor (TGF)‑β1, matrix metalloproteinase (MMP)‑9 and tissue inhibitors of metalloproteinases (TIMP)‑1 in lung tissue. α‑Smooth muscle actin (α‑SMA) activity was measured by immunohistochemistry. Airway hyperresponsiveness, lung collagen deposition, airway wall area, airway smooth muscle thickness and lung pathology were also assessed. Atorvastatin treatment led to downregulation of tTG and TREM‑1 expression in lung tissue after ovalbumin sensitization, blocked the activity of MMP‑9, vascular endothelial growth factor, nuclear factor‑κB p65, α‑SMA, HIF‑α and TGF‑β1 and up‑regulated Nrf2 expression. Furthermore, the number of lymphocytes and eosinophils in the atorvastatin group was significantly lower than that in the control group. In addition, airway hyperresponsiveness, lung collagen deposition, airway wall area, airway smooth muscle thickness and pathological changes in the lung were significantly decreased in the atorvastatin group, and tumor necrosis factor‑α, interleukin (IL)‑8, IL‑13 and IL‑17 in serum were significantly decreased. Histological results demonstrated the attenuating effect of atorvastatin on ovalbumin‑induced airway remodeling in asthma. In conclusion, the present study indicated that atorvastatin significantly alleviated ovalbumin‑induced airway remodeling in asthma by downregulating tTG and TREM‑1 expression. The marked protective effects of atorvastatin suggest its therapeutic potential in ovalbumin‑induced airway remodeling in asthma treatment.

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1	Befekadu E, Onofrei C and Colice GL: Tiotropium in asthma: A systematic review. J Asthma Allergy. 7:11–21. 2014.PubMed/NCBI
2	Roche WR, Beasley R, Williams JH and Holgate ST: Subepithelial fibrosis in the bronchi of asthmatics. Lancet. 1:520–524. 1989. View Article : Google Scholar : PubMed/NCBI
3	Aikawa T, Shimura S, Sasaki H, Ebina M and Takishima T: Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. Chest. 101:916–921. 1992. View Article : Google Scholar : PubMed/NCBI
4	Wiggs BR, Bosken C, Paré PD, James A and Hogg JC: A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis. 145:1251–1258. 1992. View Article : Google Scholar : PubMed/NCBI
5	Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, Misono K, Im MJ and Graham RM: Gh: A GTP-binding protein with transglutaminase activity and receptor signaling function. Science. 264:1593–1596. 1994. View Article : Google Scholar : PubMed/NCBI
6	Lorand L and Graham RM: Transglutaminases: Crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol. 4:140–156. 2003. View Article : Google Scholar : PubMed/NCBI
7	Iismaa SE, Mearns BM, Lorand L and Graham RM: Transglutaminases and disease: Lessons from genetically engineered mouse models and inherited disorders. Physiol Rev. 89:991–1023. 2009. View Article : Google Scholar : PubMed/NCBI
8	Griffin M, Casadio R and Bergamini CM: Transglutaminases: Nature's biological glues. Biochem J. 368:377–396. 2002. View Article : Google Scholar : PubMed/NCBI
9	Shweke N, Boulos N, Jouanneau C, Vandermeersch S, Melino G, Dussaule JC, Chatziantoniou C, Ronco P and Boffa JJ: Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration. Am J Pathol. 173:631–642. 2008. View Article : Google Scholar : PubMed/NCBI
10	Radsak MP, Salih HR, Rammensee HG and Schild H: Triggering receptor expressed on myeloid cells-1 in neutrophil inflammatory responses: Differential regulation of activation and survival. J Immunol. 172:4956–4963. 2004. View Article : Google Scholar : PubMed/NCBI
11	Bouchon A, Dietrich J and Colonna M: Cutting edge: Inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol. 164:4991–4995. 2000. View Article : Google Scholar : PubMed/NCBI
12	Bouchon A, Facchetti F, Weigand MA and Colonna M: TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 410:1103–1107. 2001. View Article : Google Scholar : PubMed/NCBI
13	Fassett RG, Robertson IK, Ball MJ, Geraghty DP and Coombes JS: Effects of atorvastatin on biomarkers of inflammation in chronic kidney disease. Clin Nephrol. 81:75–85. 2014. View Article : Google Scholar : PubMed/NCBI
14	Simpson RJ, Signorovitch J, Ramakrishnan K, Ivanova J, Birnbaum H and Kuznik A: Cardiovascular and economic outcomes after initiation of atorvastatin versus simvastatin in an employed population stratified by cardiovascular risk. Am J Ther. 18:436–448. 2011. View Article : Google Scholar : PubMed/NCBI
15	Balli U, Keles GC, Cetinkaya BO, Mercan U, Ayas B and Erdogan D: Assessment of vascular endothelial growth factor and matrix metalloproteinase-9 in the periodontium of rats treated with atorvastatin. J Periodontol. 85:178–187. 2014. View Article : Google Scholar : PubMed/NCBI
16	Feldman C: Statins for non-cystic fibrosis bronchiectasis. Lancet Respir Med. 2:431–432. 2014. View Article : Google Scholar : PubMed/NCBI
17	Jain W, Kitagaki K, Businga T, Hussain I, George C, O'shaughnessy P and Kline JN: CpG-oligodeoxynucleotides inhibit airway remodeling in a murine model of chronic asthma. J Allergy Clin Immunol. 110:867–872. 2002. View Article : Google Scholar : PubMed/NCBI
18	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
19	Liu MW, Wang YH, Qian CY and Li H: Xuebijing exerts protective effects on lung permeability leakage and lung injury by upregulating Toll-interacting protein expression in rats with sepsis. Int J Mol Med. 34:1492–1504. 2014.PubMed/NCBI
20	Mizutani N, Nabe T and Yoshino S: IL-17A promotes the exacerbation of il-33-induced airway hyperresponsiveness by enhancing neutrophilic inflammation via CXCR2 signaling in mice. J Immunol. 192:1372–1384. 2004. View Article : Google Scholar
21	Entezari M, Javdan M, Antoine DJ, Morrow DM, Sitapara RA, Patel V, Wang M, Sharma L, Gorasiya S, Zur M, et al: Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury. Redox Biol. 2:314–322. 2014. View Article : Google Scholar : PubMed/NCBI
22	Wen H, Gwathmey JK and Xie LH: Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J Hypertens. 2:34–44. 2012. View Article : Google Scholar : PubMed/NCBI
23	Wei B, Shang YX, Li M, Jiang J and Zhang H: Cytoskeleton changes of airway smooth muscle cells in juvenile rats with airway remodeling in asthma and the RhoA/ROCK signaling pathway mechanism. Genet Mol Res. 13:559–569. 2014. View Article : Google Scholar : PubMed/NCBI
24	Jamall IS, Finelli VN and Que Hee SS: A simple method to determine nanogram levels of 4-hydroyproline in biological tissues. Anal Biochem. 112:70–75. 1981. View Article : Google Scholar : PubMed/NCBI
25	Bai A, Eidelman DH, Hogg JC, James AL, Lambert RK, Ludwig MS, Martin J, McDonald DM, Mitzner WA, Okazawa M, et al: Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol (1985). 77:1011–1014. 1994.PubMed/NCBI
26	Takeda N, Kondo M, Ito S, Ito Y, Shimokata K and Kume H: Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. Am J Respir Cell Mol Biol. 35:722–729. 2006. View Article : Google Scholar : PubMed/NCBI
27	Mookerjee I, Solly NR, Royce SG, Tregear GW, Samuel CS and Tang ML: Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease. Endocrinology. 147:754–761. 2006. View Article : Google Scholar : PubMed/NCBI
28	Davies DE and Holgate ST: Asthma: The importance of epithelial mesenchymal communication in pathogenesis. Inflammation and the airway epithelium in asthma. Int J Biochem Cell Biol. 34:1520–1526. 2002. View Article : Google Scholar : PubMed/NCBI
29	Tang ML, Wilson JW, Stewart AG and Royce SG: Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 112:474–488. 2006. View Article : Google Scholar : PubMed/NCBI
30	Barnes PJ: Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci (Lond). 94:557–572. 1998. View Article : Google Scholar : PubMed/NCBI
31	Boulet LP, Turcotte H, Laviolette M, Naud F, Bernier MC, Martel S and Chakir J: Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids. Am J Respir Crit Care Med. 162:1308–1313. 2000. View Article : Google Scholar : PubMed/NCBI
32	Irwin RS and Richardson ND: Side effects with inhaled corticosteroids: The physician's perception. Chest. 130 1 Suppl:41S–53S. 2006. View Article : Google Scholar : PubMed/NCBI
33	Johnson BA, Iacono AT, Zeevi A, McCurry KR and Duncan SR: Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med. 167:1271–1278. 2003. View Article : Google Scholar : PubMed/NCBI
34	McKay A, Leung BP, McInnes IB, Thomson NC and Liew FY: A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol. 172:2903–2908. 2004. View Article : Google Scholar : PubMed/NCBI
35	Zeki AA, Franzi L, Last J and Kenyon NJ: Simvastatin inhibits airway hyperreactivity: Implications for the mevalonate pathway and beyond. Am J Respir Crit Care Med. 180:731–740. 2009. View Article : Google Scholar : PubMed/NCBI
36	Chiba Y, Arima J, Sakai H and Misawa M: Lovastatin inhibits bronchial hyperresponsiveness by reducing RhoA signaling in rat allergic asthma. Am J Physiol Lung Cell Mol Physiol. 294:L705–L713. 2008. View Article : Google Scholar : PubMed/NCBI
37	Chiba Y, Sato S and Misawa M: Inhibition of antigen-induced bronchial smooth muscle hyperresponsiveness by lovastatin in mice. J Smooth Muscle Res. 44:123–128. 2008. View Article : Google Scholar : PubMed/NCBI
38	Sánchez-Lara AC, Elliott J, Syme HM, Brown CA and Haylor JL: Feline chronic kidney disease is associated with upregulation of transglutaminase 2: A collagen cross-linking enzyme. Vet Pathol. 52:513–523. 2015. View Article : Google Scholar : PubMed/NCBI
39	Sime PJ and O'Reilly KM: Fibrosis of the lung and other tissues: New concepts in pathogenesis and treatment. Clin Immunol. 99:308–319. 2001. View Article : Google Scholar : PubMed/NCBI
40	Griffin M, Smith LL and Wynne J: Changes in transglutaminase activity in an experimental model of pulmonary fibrosis induced by paraquat. Br J Exp Pathol. 60:653–661. 1979.PubMed/NCBI
41	Olsen KC, Sapinoro RE, Kottmann RM, Kulkarni AA, Iismaa SE, Johnson GV, Thatcher TH, Phipps RP and Sime PJ: Transglutaminase 2 and its role in pulmonary fibrosis. Am J Respir Crit Care Med. 184:699–707. 2011. View Article : Google Scholar : PubMed/NCBI
42	Genua M, Rutella S, Correale C and Danese S: The triggering receptor expressed on myeloid cells (TREM) in inflammatory bowel disease pathogenesis. J Transl Med. 12:2932014. View Article : Google Scholar : PubMed/NCBI
43	Erlank H, Elmann A, Kohen R and Kanner J: Polyphenols activate Nrf2 in astrocytes via H2O2, semiquinones, and quinones. Free Radic Biol Med. 51:2319–2327. 2011. View Article : Google Scholar : PubMed/NCBI
44	Park JS, Jung JS, Jeong YH, Hyun JW, Le TK, Kim DH, Choi EC and Kim HS: Antioxidant mechanism of isoflavone metabolites in hydrogen peroxide-stimulated rat primary astrocytes: Critical role of hemeoxygenase-1 and NQO1 expression. J Neurochem. 119:909–919. 2011. View Article : Google Scholar : PubMed/NCBI
45	Hou DX, Korenori Y, Tanigawa S, Yamada-Kato T, Nagai M, He X and He J: Dynamics of Nrf2 and Keap1 in ARE-mediated NQO1 expression by wasabi 6-(methylsulfinyl)hexyl isothiocyanate. J Agric Food Chem. 59:11975–11982. 2011. View Article : Google Scholar : PubMed/NCBI
46	Lee IS, Lim J, Gal J, Kang JC, Kim HJ, Kang BY and Choi HJ: Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int. 58:153–160. 2011. View Article : Google Scholar : PubMed/NCBI
47	Barbaro MP, Spanevello A, Palladino GP, Salerno FG, Lacedonia D and Carpagnano GE: Exhaled matrix metalloproteinase-9 (MMP-9) in different biological phenotypes of asthma. Eur J Intern Med. 25:92–96. 2014. View Article : Google Scholar : PubMed/NCBI
48	Possa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA and Tibério Ide F: Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol. 303:L939–L952. 2012. View Article : Google Scholar : PubMed/NCBI
49	Yeo NK, Eom DW, Oh MY, Lim HW and Song YJ: Expression of matrix metalloproteinase 2 and 9 and tissue inhibitor of metalloproteinase 1 in nonrecurrent vs recurrent nasal polyps. Ann Allergy Asthma Immunol. 111:205–210. 2013. View Article : Google Scholar : PubMed/NCBI
50	Che Z, Zhu X, Yao C, Liu Y, Chen Y, Cao J, Liang C and Lu Y: The association between the C-509T and T869C polymorphisms of TGF-β1 gene and the risk of asthma: A meta-analysis. Hum Immunol. 75:141–150. 2014. View Article : Google Scholar : PubMed/NCBI
51	Baek KJ, Cho JY, Rosenthal P, Alexander LE, Nizet V and Broide DH: Hypoxia potentiates allergen induction of HIF-1α, chemokines, airway inflammation, TGF-β1, and airway remodeling in a mouse model. Clin Immunol. 147:27–37. 2013. View Article : Google Scholar : PubMed/NCBI
52	Mirzoeva S, Franzen CA and Pelling JC: Apigenin inhibits TGF-β-induced VEGF expression in human prostate carcinoma cells via a Smad2/3- and Src-dependent mechanism. Mol Carcinog. 53:598–609. 2014.PubMed/NCBI
53	Le Cras TD, Acciani TH, Mushaben EM, Kramer EL, Pastura PA, Hardie WD, Korfhagen TR, Sivaprasad U, Ericksen M, Gibson AM, et al: Epithelial EGF receptor signaling mediates airway hyperreactivity and remodeling in a mouse model of chronic asthma. Am J Physiol Lung Cell Mol Physiol. 300:L414–L421. 2011. View Article : Google Scholar : PubMed/NCBI
54	Park SJ, Lee KS, Lee SJ, Kim SR, Park SY, Jeon MS, Lee HB and Lee YC: L-2-Oxothiazolidine-4-carboxylic acid or α-lipoic acid attenuates airway remodeling: Involvement of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and hypoxia-inducible factor (HIF). Int J Mol Sci. 13:7915–7937. 2012. View Article : Google Scholar : PubMed/NCBI
55	Fuchimoto Y, Kanehiro A, Miyahara N, Koga H, Ikeda G, Waseda K, Tanimoto Y, Ueha S, Kataoka M, Gelfand EW and Tanimoto M: Requirement for chemokine receptor 5 in the development of allergen-induced airway hyperresponsiveness and inflammation. Am J Respir Cell Mol Biol. 45:1248–1255. 2011. View Article : Google Scholar : PubMed/NCBI