Erythromycin attenuates metalloprotease/anti-metalloprotease imbalance in cigarette smoke-induced emphysema in rats via the mitogen-activated protein kinase/nuclear factor-κB activation pathway

Zhou,Xiaoming; Gu,Dongxue; Hou,Gang

doi:10.3892/mmr.2017.6416

Erythromycin attenuates metalloprotease/anti-metalloprotease imbalance in cigarette smoke-induced emphysema in rats via the mitogen-activated protein kinase/nuclear factor-κB activation pathway

Authors:
- Xiaoming Zhou
- Dongxue Gu
- Gang Hou
View Affiliations

Affiliations: Department of Respiratory Medicine, The Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China, Department of Respiratory Medicine, People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, P.R. China, The Institute of Respiratory Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: March 30, 2017 https://doi.org/10.3892/mmr.2017.6416
Pages: 2983-2990
Copyright: © Zhou 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

The present study investigated whether erythromycin (ERY) reduces cigarette smoke (CS)-induced emphysema in rats and aimed to determine the anti-inflammatory effect of ERY, which may identify potential treatments for chronic obstructive pulmonary disease. Furthermore, the current study focused on the potential effects on the imbalance between matrix metalloprotease (MMP) and anti-MMP activity, the phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor‑κB (NF‑κB) signaling pathway. Wistar rats were divided into the following three groups (n=12 each): control (ERY vehicle only, without any CS exposure), CS (animals were exposed to CS for 12 weeks) and CS + ERY (animals were exposed to CS for 12 weeks and received 100 mg/kg/day ERY). The recruitment of inflammatory cells into the bronchoalveolar lavage fluid (BALF) and the histopathology of lung tissue from all groups was evaluated to grade the severity of the emphysema. The expression of MMP‑2, MMP‑9 and tissue inhibitor of metalloproteinase‑1 was evaluated by immunohistochemistry and western blotting. The activation of MAPKs, NF‑κB and inhibitor of NF‑κB (IκBα), in lung tissues was examined by western blotting. Treatment with ERY resulted in fewer inflammatory cells and cytokines in the BALF, and fewer emphysema‑associated changes in the lungs compared with control. The stimulus of CS promoted the phosphorylation of extracellular signal‑regulated kinase (ERK)1/2 and p38, but not c‑Jun NH2‑terminal kinase, thereby inducing the activation of the ERK/MAPK signaling pathway in rats. Furthermore, CS exposure increased the expression of NF-κB and decreased the expression of IκBα. The levels of phosphorylated ERK1/2 and p38 were significantly reduced in rats with CS‑induced emphysema when treated with ERY compared with the CS group. The results of the present study therefore indicate that oral administration of ERY may suppress CS‑induced emphysema by regulating inflammatory cytokines and the MMP/anti-MMP imbalance via the MAPK/NF-κB pathway.

View Figures

View References

1	Celli BR and MacNee W: ATS/ERS Task Force: Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J. 23:932–946. 2004. View Article : Google Scholar : PubMed/NCBI
2	Nowak D, Berger K, Lippert B, Kilgert K, Caeser M and Sandtmann R: Epidemiology and health economics of COPD across Europe: A critical analysis. Treat Respir Med. 4:381–395. 2005. View Article : Google Scholar : PubMed/NCBI
3	Fragoso CA: Epidemiology of chronic obstructive pulmonary disease (COPD) in aging populations. COPD. 13:125–129. 2016. View Article : Google Scholar : PubMed/NCBI
4	Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, et al: Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J. 27:188–207. 2006. View Article : Google Scholar : PubMed/NCBI
5	Stockley RA, O'Brien C, Pye A and Hill SL: Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD. Chest. 117:1638–1645. 2000. View Article : Google Scholar : PubMed/NCBI
6	Spurzem JR and Rennard SI: Pathogenesis of COPD. Semin Respir Crit Care Med. 26:142–153. 2005. View Article : Google Scholar : PubMed/NCBI
7	Kwiatkowska S, Noweta K, Zieba M, Nowak D and Bialasiewicz P: Enhanced exhalation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with COPD exacerbation: A prospective study. Respiration. 84:231–241. 2012. View Article : Google Scholar : PubMed/NCBI
8	Mocchegiani E, Giacconi R and Costarelli L: Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease: Genetic factors and treatment implications. Curr Opin Pulm Med. 17:(Suppl 1). S11–S19. 2011. View Article : Google Scholar : PubMed/NCBI
9	Kanoh S and Rubin BK: Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 23:590–615. 2010. View Article : Google Scholar : PubMed/NCBI
10	Mazzei T, Mini E, Novelli A and Periti P: Chemistry and mode of action of macrolides. J Antimicrob Chemother. 31:(Suppl C). S1–S9. 1993. View Article : Google Scholar
11	Perry DK, Hand WL, Edmondson DE and Lambeth JD: Role of phospholipase D-derived diradylglycerol in the activation of the human neutrophil respiratory burst oxidase. Inhibition by phosphatidic acid phosphohydrolase inhibitors. J Immunol. 149:2749–2758. 1992.PubMed/NCBI
12	Zhou Y, Tan X, Kuang W, Liu L and Wan L: Erythromycin ameliorates cigarette-smoke-induced emphysema and inflammation in rats. Transl Res. 159:464–472. 2012. View Article : Google Scholar : PubMed/NCBI
13	Birrell MA, Wong S, Catley MC and Belvisi MG: Impact of tobacco-smoke on key signaling pathways in the innate immune response in lung macrophages. J Cell Physiol. 214:27–37. 2008. View Article : Google Scholar : PubMed/NCBI
14	Moretto N, Facchinetti F, Southworth T, Civelli M, Singh D and Patacchini R: alpha, beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol. 296:L839–L848. 2009. View Article : Google Scholar : PubMed/NCBI
15	Cheng SE, Luo SF, Jou MJ, Lin CC, Kou YR, Lee IT, Hsieh HL and Yang CM: Cigarette smoke extract induces cytosolic phospholipase A2 expression via NADPH oxidase, MAPKs, AP-1, and NF-kappaB in human tracheal smooth muscle cells. Free Radic Biol Med. 46:948–960. 2009. View Article : Google Scholar : PubMed/NCBI
16	Zheng H, Liu Y, Huang T, Fang Z, Li G and He S: Development and characterization of a rat model of chronic obstructive pulmonary disease (COPD) induced by sidestream cigarette smoke. Toxicol Lett. 189:225–234. 2009. View Article : Google Scholar : PubMed/NCBI
17	Yin Y, Hou G, Li E, Wang Q and Kang J: PPARγ agonists regulate tobacco smoke-induced Toll like receptor 4 expression in alveolar macrophages. Respir Res. 15:282014. View Article : Google Scholar : PubMed/NCBI
18	Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, et al: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 176:532–555. 2007. View Article : Google Scholar : PubMed/NCBI
19	Atkinson JJ, Lutey BA, Suzuki Y, Toennies HM, Kelley DG, Kobayashi DK, Ijem WG, Deslee G, Moore CH, Jacobs ME, et al: The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema. Am J Respir Crit Care Med. 183:876–884. 2011. View Article : Google Scholar : PubMed/NCBI
20	Kanai K, Asano K, Hisamitsu T and Suzaki H: Suppression of matrix metalloproteinase production from nasal fibroblasts by macrolide antibiotics in vitro. Eur Respir J. 23:671–678. 2004. View Article : Google Scholar : PubMed/NCBI
21	Ci X, Chu X, Xu X, Li H and Deng X: Short-term roxithromycin treatment attenuates airway inflammation via MAPK/NF-κB activation in a mouse model of allergic asthma. Inflamm Res. 61:749–758. 2012. View Article : Google Scholar : PubMed/NCBI
22	Willems-Widyastuti A, Vanaudenaerde BM, Vos R, Dilisen E, Verleden SE, De Vleeschauwer SI, Vaneylen A, Mooi WJ, de Boer WI, Sharma HS and Verleden GM: Azithromycin attenuates fibroblast growth factors induced vascular endothelial growth factor via p38(MAPK) signaling in human airway smooth muscle cells. Cell Biochem Biophys. 67:331–339. 2013. View Article : Google Scholar : PubMed/NCBI
23	Singh D, Smyth L, Borrill Z, Sweeney L and Tal-Singer R: A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. J Clin Pharmacol. 50:94–100. 2010. View Article : Google Scholar : PubMed/NCBI
24	Goven D, Boutten A, Leçon-Malas V, Boczkowski J and Bonay M: Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: Roles of the MAP kinases ERK(1/2) and JNK. FEBS Lett. 583:3508–3518. 2009. View Article : Google Scholar : PubMed/NCBI
25	Chung KF: p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest. 139:1470–1479. 2011. View Article : Google Scholar : PubMed/NCBI
26	Barnes PJ and Adcock IM: Glucocorticoid resistance in inflammatory diseases. Lancet. 373:1905–1917. 2009. View Article : Google Scholar : PubMed/NCBI
27	Chen X, Zeng S, Zou J, Chen Y, Yue Z, Gao Y, Zhang L, Cao W and Liu P: Rapamycin attenuated cardiac hypertrophy induced by isoproterenol and maintained energy homeostasis via inhibiting NF-κB activation. Mediators Inflamm. 2014:8687532014. View Article : Google Scholar : PubMed/NCBI
28	Aghai ZH, Kode A, Saslow JG, Nakhla T, Farhath S, Stahl GE, Eydelman R, Strande L, Leone P and Rahman I: Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants. Pediatr Res. 62:483–488. 2007. View Article : Google Scholar : PubMed/NCBI
29	Matsumura Y, Mitani A, Suga T, Kamiya Y, Kikuchi T, Tanaka S, Aino M and Noguchi T: Azithromycin may inhibit interleukin-8 through suppression of Rac1 and a nuclear factor-kappa B pathway in KB cells stimulated with lipopolysaccharide. J Periodontol. 82:1623–1631. 2011. View Article : Google Scholar : PubMed/NCBI
30	Kobayashi Y, Wada H, Rossios C, Takagi D, Higaki M, Mikura S, Goto H, Barnes PJ and Ito K: A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-κB inhibition. J Pharmacol Exp Ther. 345:76–84. 2013. View Article : Google Scholar : PubMed/NCBI
31	Aghai ZH, Kode A, Saslow JG, Nakhla T, Farhath S, Stahl GE, Eydelman R, Strande L, Leone P and Rahman I: Azithromycin suppresses activation of nuclear factor-kappa B and synthesis of pro-inflammatory cytokines in tracheal aspirate cells from premature infants. Pediatr Res. 62:483–488. 2007. View Article : Google Scholar : PubMed/NCBI
32	Marumo S, Hoshino Y, Kiyokawa H, Tanabe N, Sato A, Ogawa E, Muro S, Hirai T and Mishima M: p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice. BMC Pulm Med. 14:792014. View Article : Google Scholar : PubMed/NCBI
33	Abe S, Nakamura H, Inoue S, Takeda H, Saito H, Kato S, Mukaida N, Matsushima K and Tomoike H: Interleukin-8 gene repression by clarithromycin is mediated by the activator protein-1 binding site in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 22:51–60. 2000. View Article : Google Scholar : PubMed/NCBI
34	Desaki M, Takizawa H, Ohtoshi T, Kasama T, Kobayashi K, Sunazuka T, Omura S, Yamamoto K and Ito K: Erythromycin suppresses nuclear factor-kappaB and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 267:124–128. 2000. View Article : Google Scholar : PubMed/NCBI
35	Kim H, Liu X, Kohyama T, Kobayashi T, Conner H, Abe S, Fang Q, Wen FQ and Rennard SI: Cigarette smoke stimulates MMP-1 production by human lung fibroblasts through the ERK1/2 pathway. COPD. 1:13–23. 2004. View Article : Google Scholar : PubMed/NCBI