Clarithromycin and dexamethasone show similar anti-inflammatory effects on distinct phenotypic chronic rhinosinusitis: an explant model study

BMC Immunology

Zheng Liu¹  Yong-Hua Cui¹  Heng Wang¹  Ping-Ping Cao¹  Jin Ma¹  Zhi-Yong Li¹  Ming Zeng¹ 

[1]Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College

[2] Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan 430030, People’s Republic of China

关键词: Innate immunity;    Tissue remodeling;    Inflammation;    Eosinophil;    Dexamethasone;    Clarithromycin;    Nasal polyps;    Chronic rhinosinusitis;   

Others  :  1215980
DOI  :  10.1186/s12865-015-0096-x

 received in 2014-12-31, accepted in 2015-05-08,  发布年份 2015

【 摘 要 】

Background

Phenotype of chronic rhinosinusitis (CRS) may be an important determining factor of the efficacy of anti-inflammatory treatments. Although both glucocorticoids and macrolide antibiotics have been recommended for the treatment of CRS, whether they have different anti-inflammatory functions for distinct phenotypic CRS has not been completely understood. The aim of this study is to compare the anti-inflammatory effects of clarithromycin and dexamethasone on sinonasal mucosal explants from different phenotypic CRS ex vivo.

Methods

Ethmoid mucosal tissues from CRSsNP patients (n = 15), and polyp tissues from eosinophilic (n = 13) and non-eosinophilic (n = 12) CRSwNP patients were cultured in an ex vivo explant model with or without dexamethasone or clarithromycin treatment for 24 h. After culture, the production and/or expression of anti-inflammatory molecules, epithelial-derived cytokines, pro-inflammatory cytokines, T helper (Th)1, Th2 and Th17 cytokines, chemokines, dendritic cell relevant markers, pattern recognition receptors (PRRs), and tissue remodeling factors were detected in tissue explants or culture supernatants by RT-PCR or ELISA, respectively.

Results

We found that both clarithromycin and dexamethasone up-regulated the production of anti-inflammatory mediators (Clara cell 10-kDa protein and interleukin (IL)-10), whereas down-regulated the production of Th2 response and eosinophilia promoting molecules (thymic stromal lymphopoietin, IL-25, IL-33, CD80, CD86, OX40 ligand, programmed cell death ligand 1, CCL17, CCL22, CCL11, CCL5, IL-5, IL-13, and eosinophilic cationic protein) and Th1 response and neutrophilia promoting molecules (CXCL8, CXCL5, CXCL10, CXCL9, interferon-γ, and IL-12), from sinonasal mucosa from distinct phenotypic CRS. In contrast, they had no effect on IL-17A production. The expression of PRRs (Toll-like receptors and melanoma differentiation-associated gene 5) was induced, and the production of tissue remodeling factors (transforming growth factor-β1, epidermal growth factor, basic fibroblast growth factor, platelet derived growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9) was suppressed, in different phenotypic CRS by dexamethasone and clarithromycin in comparable extent.

Conclusions

Out of our expectation, our explant model study discovered herein that glucocorticoids and macrolides likely exerted similar regulatory actions on CRS and most of their effects did not vary by the phenotypes of CRS.

【 授权许可】

   
2015 Zeng et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F et al.. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl. 2012; 23:1-298.
• [2]Cao PP, Li HB, Wang BF, Wang SB, You XJ, Cui YH et al.. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol. 2009; 124:478-84.
• [3]Zhang N, Van Zele T, Perez-Novo C, Van Bruaene N, Holtappels G, DeRuyck N et al.. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J Allergy Clin Immunol. 2008; 122:961-8.
• [4]Alobid I, Mullol J. Role of medical therapy in the management of nasal polyps. Curr Allergy Asthma Rep. 2012; 12:144-53.
• [5]Zen M, Canova M, Campana C, Bettio S, Nalotto L, Rampudda M et al.. The kaleidoscope of glucorticoid effects on immune system. Autoimmun Rev. 2011; 10:305-10.
• [6]Tamaoki J. The effects of macrolides on inflammatory cells. Chest. 2004; 125:41S-50.
• [7]Tauber SC, Nau R. Immunomodulatory properties of antibiotics. Curr Mol Pharmacol. 2008; 1:68-79.
• [8]Cervin A, Wallwork B. Efficacy and safety of long-term antibiotics (macrolides) for the treatment of chronic rhinosinusitis. Curr Allergy Asthma Rep. 2014; 14:416.
• [9]Wallwork B, Coman W, Mackay-Sim A, Greiff L, Cervin A. A double-blind, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Laryngoscope. 2006; 116:189-93.
• [10]Videler WJ, Badia L, Harvey RJ, Gane S, Georgalas C, van der Meulen FW et al.. Lack of efficacy of long-term, low-dose azithromycin in chronic rhinosinusitis: a randomized controlled trial. Allergy. 2011; 66:1457-68.
• [11]Shi LL, Song J, Xiong P, Cao PP, Liao B, Ma J et al.. Disease-specific T-helper cell polarizing function of lesional dendritic cells in different types of chronic rhinosinusitis with nasal polyps. Am J Respir Crit Care Med. 2014; 190:628-38.
• [12]Derycke L, Eyerich S, Van Crombruggen K, Pérez-Novo C, Holtappels G, Deruyck N et al.. Mixed T helper cell signatures in chronic rhinosinusitis with and without polyps. PLoS One. 2014; 9: Article ID e97581
• [13]Peters AT, Kato A, Zhang N, Conley DB, Suh L, Tancowny B et al.. Evidence for altered activity of the IL-6 pathway in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2010; 125:397-403.
• [14]Wen W, Liu W, Zhang L, Bai J, Fan Y, Xia W et al.. Nasal Health Group, China (NHGC): Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy. J Allergy Clin Immunol. 2012; 129:1522-8.
• [15]Luo Q, Chen F, Liu W, Li Z, Xu R, Fan Y et al.. Nasal Health Group, China (NHGC): evaluation of long-term clarithromycin treatment in adult Chinese patients with chronic rhinosinusitis without nasal polyps. ORL J Otorhinolaryngol Relat Spec. 2011; 73:206-11.
• [16]Bleier BS, Mulligan RM, Schlosser RJ. Primary human sinonasal epithelial cell culture model for topical drug delivery in patients with chronic rhinosinusitis with nasal polyposis. J Pharm Pharmacol. 2012; 64:449-56.
• [17]Wallwork B, Coman W, Feron F, Mackay-Sim A, Cervin A. Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis. Laryngoscope. 2002; 112:1827-30.
• [18]Liu Z, Lu X, Zhang XH, Bochner BS, Long XB, Zhang F et al.. Clara cell 10-kDa protein expression in chronic rhinosinusitis and its cytokine-driven regulation in sinonasal mucosa. Allergy. 2009; 64:149-57.
• [19]Li HB, Cai KM, Liu Z, Xia JH, Zhang Y, Xu R et al.. Foxp3+ T regulatory cells (Tregs) are increased in nasal polyps (NP) after treatment with intranasal steroid. Clin Immunol. 2008; 129:394-400.
• [20]Saenz SA, Taylor BC, Artis D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites. Immunol Rev. 2008; 226:172-90.
• [21]Cervin A, Wallwork B, Mackay-Sim A, Coman WB, Greiff L. Effects of long-term clarithromycin treatment on lavage-fluid markers of inflammation in chronic rhinosinusitis. Clin Physiol Funct Imaging. 2009; 29:136-42.
• [22]Wallwork B, Coman W, Mackay-Sim A, Cervin A. Effect of clarithromycin on nuclear factor-kappa B and transforming growth factor-beta in chronic rhinosinusitis. Laryngoscope. 2004; 114:286-90.
• [23]Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope. 1997; 107:1661-6.
• [24]Zhang N, Truong-Tran QA, Tancowny B, Harris KE, Schleimer RP. Glucocorticoids enhance or spare innate immunity: effects in airway epithelium are mediated by CCAAT/enhancer binding proteins. J Immunol. 2007; 179:578-89.
• [25]Homma T, Kato A, Hashimoto N, Batchelor J, Yoshikawa M, Imai S et al.. Corticosteroid and cytokines synergistically enhance toll-like receptor 2 expression in respiratory epithelial cells. Am J Respir Cell Mol Biol. 2004; 31:463-9.
• [26]Shi LL, Xiong P, Zhang L, Cao PP, Liao B, Lu X et al.. Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy. 2013; 68:101-9.
• [27]Van Bruaene N, Bachert C. Tissue remodeling in chronic rhinosinusitis. Curr Opin Allergy Clin Immunol. 2011; 11:8-11.
• [28]Pawankar R, Nonaka M. Inflammatory mechanisms and remodeling in chronic rhinosinusitis and nasal polyps. Curr Allergy Asthma Rep. 2007; 7:202-8.
• [29]Li X, Meng J, Qiao X, Liu Y, Liu F, Zhang N et al.. Expression of TGF, matrix metalloproteinases and tissue inhibitors in Chinese chronic rhinosinusitis. J Allergy Clin Immunol. 2010; 125:1061-8.
• [30]Hata Y, Sassa Y, Kita T, Miura M, Kano K, Kawahara S et al.. Vascular endothelial growth factor expression by hyalocytes and its regulation by glucocorticoid. Br J Ophthalmol. 2008; 92:1540-4.
• [31]Yuksel H, Yilmaz O, Karaman M, Bagriyanik HA, Firinci F, Kiray M et al.. Role of vascular endothelial growth factor antagonism on airway remodeling in asthma. Ann Allergy Asthma Immunol. 2013; 110:150-5.
• [32]Kimura M, Moteki H, Ogihara M. Inhibitory effects of dexamethasone on epidermal growth factor-induced DNA synthesis and proliferation in primary cultures of adult rat hepatocytes. Biol Pharm Bull. 2011; 34:682-7.
• [33]Cao PP, Zhang YN, Liao B, Ma J, Wang BF, Wang H et al.. Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not non-eosinophilic, chronic rhinosinusitis with nasal polyps. Clin Exp Allergy. 2014; 44:690-700.
• [34]Kroegel C. Global Initiative for Asthma (GINA) guidelines: 15 years of application. Expert Rev Clin Immunol. 2009; 5:239-49.
• [35]Zhang XH, Lu X, Long XB, You XJ, Gao QX, Cui YH et al.. Chronic rhinosinusitis with and without nasal polyps is associated with decreased expression of glucocorticoid-induced leucine zipper. Clin Exp Allergy. 2009; 39:647-54.
• [36]Liu Z, Lu X, Wang H, You XJ, Gao QX, Cui YH. Group II subfamily secretory phospholipase A2 enzymes: expression in chronic rhinosinusitis with and without nasal polyps. Allergy. 2007; 62:999-1006.
• [37]Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A et al.. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013; 123:2873-92.
• [38]Sur P, Sribnick EA, Patel SJ, Ray SK, Banik NL. Dexamethasone decreases temozolomide-induced apoptosis in human gliobastoma T98G cells. Glia. 2005; 50:160-7.
• [39]Lu X, Zhang XH, Wang H, Long XB, You XJ, Gao QX et al.. Expression of osteopontin in chronic rhinosinusitis with and without nasal polyps. Allergy. 2009; 64:104-11.