Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
December-2017 Volume 14 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
December-2017 Volume 14 Issue 6

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article Open Access

Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps

  • Authors:
    • Shuibin Wang
    • Hanwu Zhang
    • Zulian Xi
    • Jingjing Huang
    • Jun Nie
    • Bin Zhou
    • Yuqin Deng
    • Zezhang Tao
  • View Affiliations / Copyright

    Affiliations: Department of Otolaryngology‑Head and Neck Surgery, Yichang Yiling Hospital, Yichang, Hubei 443100, P.R. China, Department of Otolaryngology‑Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 5275-5282
    |
    Published online on: September 27, 2017
       https://doi.org/10.3892/etm.2017.5208
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Research has identified that gram‑negative bacteria have an important role in refractory nasal polyps. In the present study, lipopolysaccharide (LPS) was used to establish a mouse model with neutrophilic nasal polyps in order to explore the effect and mechanism of LPS on the formation of neutrophilic nasal polyps in mice. A total of 5 or 10 µg of LPS was dropped into the nasal cavities of C57BL/6J mice in order to establish animal models with neutrophilic nasal polyps. Histological staining, toll‑like receptor 4 (TLR4), cluster of differentiation 68 for macrophages and myeloperoxidase for neutrophil immunohistochemistry were used to observe histopathological changes in the nasal mucosa. The expression levels of cytokines, including interferon (IFN)‑γ, tumor necrosis factor (TNF)‑α, interleukin (IL)‑4 and IL‑17 in the nasal lavage fluid, were detected by ELISA. Compared with the control group, mice in the LPS groups exhibited significant mucosa epithelial cell damage and nasal polyp formation. Furthermore, TLR4+ cells, macrophages, neutrophils and significantly increased levels of IFN‑γ, TNF‑α, and IL‑17 in the nasal lavage fluids were indicated (all P=0.008). These findings indicated that LPS is able to activate the TLR4 receptor pathway to induce the formation of neutrophilic nasal polyps in mice. Additionally, LPS administration was accompanied by a significant increase in the number of macrophages, T helper (Th) 1 and Th17‑related cytokines (P=0.009, P=0.008 and P=0.008, respectively). Therefore, the present model is commensurate with the characteristics of primary nasal polyps that have been identified in the Asian population.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

View References

1 

Cao PP, Li HB, Wang BF, Wang SB, You XJ, Cui YH, Wang DY, Desrosiers M and Liu Z: Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol. 124(478–484): 484.e1–e2. 2009.

2 

Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P, et al: European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl. 23(3): p preceding table of contents. 1–298. 2012.

3 

Wen W, Liu W, Zhang L, Bai J, Fan Y, Xia W, Luo Q, Zheng J, Wang H, Li Z, et al: Increased neutrophilia in nasal polyps reduces the response to oral corticosteroid therapy. J Allergy Clin Immunol. 129:1522–1528.e5. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Smith KA and Rudmik L: Impact of continued medical therapy in patients with refractory chronic rhinosinusitis. Int Forum Allergy Rhinol. 4:34–38. 2014. View Article : Google Scholar : PubMed/NCBI

5 

Kim DW, Khalmuratova R, Hur DG, Jeon SY, Kim SW, Shin HW, Lee CH and Rhee CS: Staphylococcus aureus enterotoxin B contributes to induction of nasal polypoid lesions in an allergic rhinosinusitis murine model. Am J Rhinol Allergy. 25:e255–e261. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Kim DH, Jeon EJ, Park SN, Park KH, Park YS and Yeo SW: Effects of a tumor necrosis factor-a antagonist on experimentally induced rhinosinusitis. J Biomed Biotechnol. 2011:3604572011. View Article : Google Scholar : PubMed/NCBI

7 

Wang H, Lu X, Cao PP, Chu Y, Long XB, Zhang XH, You XJ, Cui YH and Liu Z: Histological and immunological observations of bacterial and allergic chronic rhinosinusitis in the mouse. Am J Rhinol. 22:343–348. 2008. View Article : Google Scholar : PubMed/NCBI

8 

Jin M, Gu Z, Bian Z, Yang J, Cao Z, Yu X and Guo G: Developing a mouse model of acute bacterial rhinosinusitis. Eur Arch Otorhinolaryngol. 268:857–861. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Kim SW, Kim JH, Jung MH, Hur DG, Lee HK, Jeon SY and Kim DW: Periostin may play a protective role in the development of eosinophilic chronic rhinosinusitis with nasal polyps in a mouse model. Laryngoscope. 123:1075–1081. 2013. View Article : Google Scholar : PubMed/NCBI

10 

Rylander R: Endotoxin in the environment-exposure and effects. J Endotoxin Res. 8:241–252. 2002. View Article : Google Scholar : PubMed/NCBI

11 

Grindler D, Thomas C, Hall GS and Batra PS: The role of Stenotrophomonas maltophilia in refractory chronic rhinosinusitis. Am J Rhinol Allergy. 24:200–204. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Rombaux P, Collet S, Hamoir M, Eloy P, Bertrand B, Jamart F and Gigi J: The role of nasal cavity disinfection in the bacteriology of chronic sinusitis. Rhinology. 43:125–129. 2005.PubMed/NCBI

13 

Wang SB, Deng YQ, Ren J, Xiao BK, Liu Z and Tao ZZ: Exogenous interleukin-10 alleviates allergic inflammation but inhibits local interleukin-10 expression in a mouse allergic rhinitis model. BMC Immunol. 15:92014. View Article : Google Scholar : PubMed/NCBI

14 

Peterson S, Poposki JA, Nagarkar DR, Chustz RT, Peters AT, Suh LA, Carter R, Norton J, Harris KE, Grammer LC, et al: Increased expression of CC chemokine ligand 18 in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 129(119–127): e1–e9. 2012.

15 

Potter PC and Pawankar R: Indications, efficacy, and safety of intranasal corticosteriods in rhinosinusitis. World Allergy Organ J. 5 Suppl 1:S14–S17. 2012. View Article : Google Scholar

16 

Mitroi M, Căpitănescu A, Georgescu CV, Mogoantă CA, Popescu C, Georgescu M, Mitroi G and Ioniţă E: Expression pattern of CK7 and CK20 in nasal polyps, at patients with chronic rhinosinusitis with nasal polyposis. Rom J Morphol Embryol. 52 3 Suppl:S1051–S1057. 2011.

17 

Dlugaszewska J, Leszczynska M, Lenkowski M, Tatarska A, Pastusiak T and Szyfter W: The pathophysiological role of bacterial biofilms in chronic sinusitis. Eur Arch Otorhinolaryngol. 273:1989–1994. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Rom D, Snidvongs K, Sacks PL, Dalgorf D, Pratt E, Earls P, Sacks R and Harvey RJ: The impact of culturable bacterial community on histopathology in chronic rhinosinusitis. Int Forum Allergy Rhinol. 4:29–33. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Bhattacharyya N and Kepnes LJ: The microbiology of recurrent rhinosinusitis after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg. 125:1117–1120. 1999. View Article : Google Scholar : PubMed/NCBI

20 

Curran CS, Demick KP and Mansfield JM: Lactoferrin activates macrophages via TLR4-dependent and -independent signaling pathways. Cell Immunol. 242:23–30. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Inubushi T, Kawazoe A, Miyauchi M, Kudo Y, Ao M, Ishikado A, Makino T and Takata T: Molecular mechanisms of the inhibitory effects of bovine lactoferrin on lipopolysaccharide-mediated osteoclastogenesis. J Biol Chem. 287:23527–23536. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Guha M and Mackman N: LPS induction of gene expression in human monocytes. Cell Signal. 13:85–94. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Tsukamoto H, Fukudome K, Takao S, Tsuneyoshi N and Kimoto M: Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 dimerization enables rapid signal transduction against lipopolysaccharide stimulation on membrane-associated CD14-expressing cells. Int Immunol. 22:271–280. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Tanno D, Akahori Y, Toyama M, Sato K, Kudo D, Abe Y, Miyasaka T, Yamamoto H, Ishii K, Kanno E, et al: Involvement of Gr-1 dull+ cells in the production of TNF-α and IL-17 and exacerbated systemic inflammatory response caused by lipopolysaccharide. Inflammation. 37:186–195. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Cao AT, Yao S, Stefka AT, Liu Z, Qin H, Liu H, Evans-Marin HL, Elson CO, Nagler CR and Cong Y: TLR4 regulates IFN-γ and IL-17 production by both thymic and induced Foxp3+ Tregs during intestinal inflammation. J Leukoc Biol. 96:895–905. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Barboza R, Câmara NO, Gomes E, Sá-Nunes A, Florsheim E, Mirotti L, Labrada A, Alcântara-Neves NM and Russo M: Endotoxin exposure during sensitization to blomia tropicalis allergens shifts TH2 immunity towards a TH17-mediated airway neutrophilic inflammation: Role of TLR4 and TLR2. PLoS One. 8:e671152013. View Article : Google Scholar : PubMed/NCBI

27 

Elass-Rochard E, Legrand D, Salmon V, Roseanu A, Trif M, Tobias PS, Mazurier J and Spik G: Lactoferrin inhibits the endotoxin interaction with CD14 by competition with the lipopolysaccharide-binding protein. Infect Immun. 66:486–491. 1998.PubMed/NCBI

28 

Qin H, Holdbrooks AT, Liu Y, Reynolds SL, Yanagisawa LL and Benveniste EN: SOCS3 deficiency promotes M1 macrophage polarization and inflammation. J Immunol. 189:3439–3448. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Al Faraj A, Sultana Shaik A, Pureza MA, Alnafea M and Halwani R: Preferential macrophage recruitment and polarization in LPS-induced animal model for COPD: Noninvasive tracking using MRI. PLoS One. 9:e908292014. View Article : Google Scholar : PubMed/NCBI

30 

Dong L, Li H, Wang S and Li Y: Different doses of lipopolysaccharides regulate the lung inflammation of asthmatic mice via TLR4 pathway in alveolar macrophages. J Asthma. 46:229–233. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Kim YK, Oh SY, Jeon SG, Park HW, Lee SY, Chun EY, Bang B, Lee HS, Oh MH, Kim YS, et al: Airway exposure levels of lipopolysaccharide determine type 1 versus type 2 experimental asthma. J Immunol. 178:5375–5382. 2007. View Article : Google Scholar : PubMed/NCBI

32 

Lee S, Hwang HJ and Kim Y: Modeling the role of TGF-β in regulation of the Th17 phenotype in the LPS-driven immune system. Bull Math Biol. 76:1045–1080. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Zhang Q, Wang CS, Han DM, Sy C, Huang Q, Sun Y, Fan EZ, Li Y and Zhou B: Differential expression of Toll-like receptor pathway genes in chronic rhinosinusitis with or without nasal polyps. Acta Otolaryngol. 133:165–173. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Tengroth L, Millrud CR, Kvarnhammar AM, Kumlien Georén S, Latif L and Cardell LO: Functional effects of Toll-like receptor (TLR)3, 7, 9, RIG-I and MDA-5 stimulation in nasal epithelial cells. PLoS One. 9:e982392014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Wang S, Zhang H, Xi Z, Huang J, Nie J, Zhou B, Deng Y and Tao Z: Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps. Exp Ther Med 14: 5275-5282, 2017.
APA
Wang, S., Zhang, H., Xi, Z., Huang, J., Nie, J., Zhou, B. ... Tao, Z. (2017). Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps. Experimental and Therapeutic Medicine, 14, 5275-5282. https://doi.org/10.3892/etm.2017.5208
MLA
Wang, S., Zhang, H., Xi, Z., Huang, J., Nie, J., Zhou, B., Deng, Y., Tao, Z."Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps". Experimental and Therapeutic Medicine 14.6 (2017): 5275-5282.
Chicago
Wang, S., Zhang, H., Xi, Z., Huang, J., Nie, J., Zhou, B., Deng, Y., Tao, Z."Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps". Experimental and Therapeutic Medicine 14, no. 6 (2017): 5275-5282. https://doi.org/10.3892/etm.2017.5208
Copy and paste a formatted citation
x
Spandidos Publications style
Wang S, Zhang H, Xi Z, Huang J, Nie J, Zhou B, Deng Y and Tao Z: Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps. Exp Ther Med 14: 5275-5282, 2017.
APA
Wang, S., Zhang, H., Xi, Z., Huang, J., Nie, J., Zhou, B. ... Tao, Z. (2017). Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps. Experimental and Therapeutic Medicine, 14, 5275-5282. https://doi.org/10.3892/etm.2017.5208
MLA
Wang, S., Zhang, H., Xi, Z., Huang, J., Nie, J., Zhou, B., Deng, Y., Tao, Z."Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps". Experimental and Therapeutic Medicine 14.6 (2017): 5275-5282.
Chicago
Wang, S., Zhang, H., Xi, Z., Huang, J., Nie, J., Zhou, B., Deng, Y., Tao, Z."Establishment of a mouse model of lipopolysaccharide‑induced neutrophilic nasal polyps". Experimental and Therapeutic Medicine 14, no. 6 (2017): 5275-5282. https://doi.org/10.3892/etm.2017.5208
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team