Anti-Inflammatory Effects of a Cordyceps sinensis Mycelium Culture Extract (Cs-4) on Rodent Models of Allergic Rhinitis and Asthma

Jihang Chen, Wing Man Chan, Hoi Yan Leung, Pou Kuan Leong, Choly Tat Ming Yan, Kam Ming Ko, Jihang Chen, Wing Man Chan, Hoi Yan Leung, Pou Kuan Leong, Choly Tat Ming Yan, Kam Ming Ko

Abstract

Allergic rhinitis and asthma are common chronic allergic diseases of the respiratory tract, which are accompanied by immunoglobulin E (IgE)-mediated inflammation and the involvement of type 2 T helper cells, mast cells, and eosinophils. Cordyceps sinensis (Berk.) Sacc is a fungal parasite on the larva of Lepidoptera. It has been considered to be a health-promoting food and, also, one of the best-known herbal remedies for the treatment of airway diseases, such as asthma and lung inflammation. In the present study, we demonstrated the antiallergic rhinitis effect of Cs-4, a water extract prepared from the mycelium culture of Cordyceps sinensis (Berk) Sacc, on ovalbumin (OVA)-induced allergic rhinitis in mice and the anti-asthmatic effect of Cs-4 in a rat model of asthma. Treatment with Cs-4 suppressed the nasal symptoms induced in OVA-sensitized and challenged mice. The inhibition was associated with a reduction in IgE/OVA-IgE and interleukin (IL)-4/IL-13 levels in the nasal fluid. Cs-4 treatment also decreased airway responsiveness and ameliorated the scratching behavior in capsaicin-challenged rats. It also reduced plasma IgE levels, as well as IgE and eosinophil peroxidase levels, in the bronchoalveolar fluid. Cs-4 treatment completely suppressed the increases in IL-4, IL-5, and IL-13 levels in rat lung tissue. In conclusion, our results suggest that Cs-4 has the potential to alleviate immune hypersensitivity reactions in allergic rhinitis and asthma.

Keywords: Cordyceps; allergic rhinitis; anti-inflammatory effect; asthma.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The effect of Cs-4 on the nasal symptoms of ovalbumin (OVA)-sensitized and challenged mice. Nasal symptoms of (a) nose rubbing and (b) sneezing were observed. Each bar represents the mean ± S.E.M., with n = 5. * Significantly different from the non-OVA control group. # Significantly different from the OVA-sensitized and challenged control group. DEX: dexamethasone.
Figure 2
Figure 2
The effect of Cs-4 on (a) the levels of immunoglobulin E (IgE) and (b) OVA-specific IgE in the lavage nasal fluid (NFL) of OVA-sensitized and challenged mice. Each bar represents the mean ± S.E.M., with n = 5. * Significantly different from the non-OVA control group. # Significantly different from the OVA-sensitized and challenged control group.
Figure 3
Figure 3
The effect of Cs-4 on (a) the levels of interleukin (IL)-4 and (b) IL-13 in the NLF of OVA-sensitized and challenged mice. Each bar represents the mean ± S.E.M., with n = 5. * Significantly different from the non-OVA control group. # Significantly different from the OVA-sensitized and challenged control group.
Figure 4
Figure 4
The effects of Cs-4 on the C48/80-activated β-hexosaminidase release in rat peritoneal mast cells (RPMC) in vitro. Each bar represents the mean ± SD, with n = 6. * Significantly different from the control group. # Significantly different from the C48/80 non-Cs-4-incubated control group.
Figure 5
Figure 5
The effects of Cs-4 on the C48/80-activated histamine release in rat RPMC in vitro. Each bar represents the mean ± SD, with n = 6. * Significantly different from the control group. # Significantly different from the C48/80 non-Cs-4-incubated control group.
Figure 6
Figure 6
Representative images of the tracheal or bronchial rings taken before (initial) and after 1-μM methacholine (Mch) was added.
Figure 7
Figure 7
The effect of Cs-4 on the scratching behavior of capsaicin-challenged rats. The rat model of asthma was established, and scratching behavior was scored as described in the Materials and Methods. Each bar represents the mean ± S.E.M., with n = 8. * Significantly different from the noncapsaicin control group. # Significantly different from the capsaicin control group.
Figure 8
Figure 8
The effect of Cs-4 on the plasma IgE levels in capsaicin-challenged rats. Data were expressed as the control percent of noncapsaicin rats, with the control value being 16.9 ± 0.47 ng/mL. Each bar represents the mean ± S.E.M., with n = 8. * Significantly different from the noncapsaicin control group. # Significantly different from the capsaicin control group.
Figure 9
Figure 9
The effect of Cs-4 on the (a) IgE level and (b) eosinophil peroxidase (EPO) level in the bronchoalveolar (BAL) fluid of capsaicin-challenged rats. Data were expressed as the control percent of noncapsaicin rats, with the control value being (a) 13.3 ± 0.58 ng/mL IgE and (b) 0.600 ± 0.034 ng/mL EPO. Each bar represents the mean ± S.E.M., with n = 8. * Significantly different from the noncapsaicin control group. # Significantly different from the capsaicin control group.
Figure 10
Figure 10
The effect of Cs-4 on various cytokine levels in the lung tissues of capsaicin-challenged rats. Data were expressed as the control percent of noncapsaicin rats, with the control values being (a) 367.6 ± 15.9 pg/mL (interleukin (IL)-4), (b) 368.1 ± 9.22 (IL-5), (c) 18.7 ± 0.67 pg/mL (IL-13), (d) 354.8 ± 7.39 pg/mL (tumor necrosis factor (TNF)-α), and (e) 745.6 ± 10.37 (interferon (IFN)-γ). Each bar represents the mean ± S.E.M., with n = 8. * Significantly different from the noncapsaicin control group. # Significantly different from the capsaicin control group.
Figure 10
Figure 10
The effect of Cs-4 on various cytokine levels in the lung tissues of capsaicin-challenged rats. Data were expressed as the control percent of noncapsaicin rats, with the control values being (a) 367.6 ± 15.9 pg/mL (interleukin (IL)-4), (b) 368.1 ± 9.22 (IL-5), (c) 18.7 ± 0.67 pg/mL (IL-13), (d) 354.8 ± 7.39 pg/mL (tumor necrosis factor (TNF)-α), and (e) 745.6 ± 10.37 (interferon (IFN)-γ). Each bar represents the mean ± S.E.M., with n = 8. * Significantly different from the noncapsaicin control group. # Significantly different from the capsaicin control group.

References

    1. Dharmage S.C., Perret J.L., Custovic A. Epidemiology of Asthma in Children and Adults. Front. Pediatr. 2019;7:246. doi: 10.3389/fped.2019.00246.
    1. Egan M., Bunyavanich S. Allergic rhinitis: The “Ghost Diagnosis” in patients with asthma. Asthma Res. Pract. 2015;1:8. doi: 10.1186/s40733-015-0008-0.
    1. Aun M.V., Bonamichi-Santos R., Arantes-Costa F.M., Kalil J., Giavina-Bianchi P. Animal models of asthma: Utility and limitations. J. Asthma Allergy. 2017;10:293–301. doi: 10.2147/JAA.S121092.
    1. Price D. Asthma and allergic rhinitis: Linked in treatment and outcomes. Ann. Thorac. Med. 2010;5:63–64. doi: 10.4103/1817-1737.62467.
    1. Khan D.A. Allergic rhinitis and asthma: Epidemiology and common pathophysiology. Allergy Asthma Proc. 2014;35:357–361. doi: 10.2500/aap.2014.35.3794.
    1. Galli S.J., Tsai M., Piliponsky A.M. The development of allergic inflammation. Nature. 2008;454:445–454. doi: 10.1038/nature07204.
    1. Gilfillan A.M., Tkaczyk C. Integrated signaling pathways for mast-cell activation. Nat. Rev. Immunol. 2006;6:218–230. doi: 10.1038/nri1782.
    1. Kay A.B. Allergy and allergic diseases. First of two parts. N. Engl. J. Med. 2001;344:30–37. doi: 10.1056/NEJM200101043440106.
    1. Olatunji O.J., Tang J., Tola A., Auberon F., Oluwaniyi O., Ouyang Z. The genus Cordyceps: An extensive review of its traditional uses, phytochemistry and pharmacology. Fitoterapia. 2018;129:293–316. doi: 10.1016/j.fitote.2018.05.010.
    1. Koh J.H., Suh H.J., Ahn T.S. Hot-water extract from mycelia of Cordyceps sinensis as a substitute for antibiotic growth promoters. Biotechnol. Lett. 2003;25:585–590. doi: 10.1023/A:1022893000418.
    1. Rao Y.K., Fang S.H., Tzeng Y.M. Evaluation of the anti-inflammatory and anti-proliferation tumoral cells activities of Antrodia camphorata, Cordyceps sinensis, and Cinnamomum osmophloeum bark extracts. J. Ethnopharmacol. 2007;114:78–85. doi: 10.1016/j.jep.2007.07.028.
    1. Chiou Y.L., Lin C.Y. The extract of Cordyceps sinensis inhibited airway inflammation by blocking NF-kappaB activity. Inflammation. 2012;35:985–993. doi: 10.1007/s10753-011-9402-9.
    1. Heo J.C., Nam S.H., Nam D.Y., Kim J.G., Lee K.G., Yeo J.H., Yoon C.K., Park C.H., Lee S.H. Anti-asthmatic activities in mycelial extract and culture filtrate of Cordyceps sphecocephala J201. Int. J. Mol. Med. 2010;26:351–356.
    1. Amin K., Janson C., Bystrom J. Role of Eosinophil Granulocytes in Allergic Airway Inflammation Endotypes. Scand. J. Immunol. 2016;84:75–85. doi: 10.1111/sji.12448.
    1. Kudo M., Melton A.C., Chen C., Engler M.B., Huang K.E., Ren X., Wang Y., Bernstein X., Li J.T., Atabai K., et al. IL-17A produced by alphabeta T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat. Med. 2012;18:547–554. doi: 10.1038/nm.2684.
    1. Liang K.L., Jiang R.S., Wang R.C., Koo M., Chen S.C., Huang W.C., Yeh Y.C. Upper airway inflammation exacerbates bronchial hyperreactivity in mouse models of rhinosinusitis and allergic asthma. Int. Forum Allergy Rhinol. 2013;3:532–542. doi: 10.1002/alr.21160.
    1. Jeong K.T., Kim S.G., Lee J., Park Y.N., Park H.H., Park N.Y., Kim K.J., Lee H., Lee Y.J., Lee E. Anti-allergic effect of a Korean traditional medicine, Biyeom-Tang on mast cells and allergic rhinitis. BMC Complement. Altern. Med. 2014;14:54. doi: 10.1186/1472-6882-14-54.
    1. Kuehn H.S., Radinger M., Gilfillan A.M. Measuring mast cell mediator release. Curr. Protoc. Immunol. 2010;91:7.38.1–7.38.9. doi: 10.1002/0471142735.im0738s91.
    1. Chong W., Feng X.Y., Zhen G.Z., Dan L., Yue D. Inhibition of mast cell degranulation by saponins from Gleditsia sinensis--structure-activity relationships. Nat. Prod. Commun. 2009;4:777–782. doi: 10.1177/1934578X0900400608.
    1. Huang L., Pi J., Wu J., Zhou H., Cai J., Li T., Liu L. A rapid and sensitive assay based on particle analysis for cell degranulation detection in basophils and mast cells. Pharmacol. Res. 2016;111:374–383. doi: 10.1016/j.phrs.2016.05.033.
    1. Choi Y.H., Yan G.H., Chai O.H., Song C.H. Inhibitory effects of curcumin on passive cutaneous anaphylactoid response and compound 48/80-induced mast cell activation. Anat. Cell Biol. 2010;43:36–43. doi: 10.5115/acb.2010.43.1.36.
    1. Georas S.N., Guo J., De Fanis U., Casolaro V. T-helper cell type-2 regulation in allergic disease. Eur. Respir. J. 2005;26:1119–1137. doi: 10.1183/09031936.05.00006005.
    1. Akdis M., Aab A., Altunbulakli C., Azkur K., Costa R.A., Crameri R., Duan S., Eiwegger T., Eljaszewicz A., Ferstl R., et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases. J. Allergy Clin. Immunol. 2016;138:984–1010. doi: 10.1016/j.jaci.2016.06.033.
    1. Leonard C., Tormey V., Burke C., Poulter L.W. Allergen-induced cytokine production in atopic disease and its relationship to disease severity. Am. J. Respir. Cell Mol. Biol. 1997;17:368–375. doi: 10.1165/ajrcmb.17.3.2797.
    1. Koning H., Neijens H.J., Baert M.R., Oranje A.P., Savelkoul H.E. T cell subsets and cytokines in allergic and non-allergic children. I. Analysis of IL-4, IFN-gamma and IL-13 mRNA expression and protein production. Cytokine. 1997;9:416–426. doi: 10.1006/cyto.1996.0184.
    1. Keeney G.E., Gray M.P., Morrison A.K., Levas M.N., Kessler E.A., Hill G.D., Gorelick M.H., Jackson J.L. Dexamethason for acute asthma exacerations in children: A meta-analysis. Pediatrics. 2014;133:433–439. doi: 10.1542/peds.2013-2273.
    1. Hopkins R.L., Leinung M. Exogenous Cushing’s syndrome and glucocorticoid withdrawal. Endocrinol. Metab. Clin. N. Am. 2005;34:371–384. doi: 10.1016/j.ecl.2005.01.013.
    1. Malkawi A.K., Alzoubi K.H., Jacob M., Matic G., Ali A., Faraj A., Almuhanna F., Dasouki M., Rahman A.M.A. Metabolomics based profiling of dexamethasone side effects in rats. Front. Parmacol. 2018;9:46. doi: 10.3389/fphar.2018.00046.
    1. Kim H.Y., Jee H., Yeom J.H., Jeong H.J., Kim H.M. The ameliorative effect of AST2017-01 in an ovalbumin-induced allergic rhinitis animal model. Inflamm. Res. 2019;68:387–395. doi: 10.1007/s00011-019-01226-y.
    1. Hsu C.H., Sun H.L., Sheu J.M., Ku M.S., Hu C.M., Chan Y., Lue K.H. Effects of the immunomodulatory agent Cordyceps militaris on airway inflammation in a mouse asthma model. Pediatr. Neonatol. 2008;49:171–178. doi: 10.1016/S1875-9572(09)60004-8.
    1. Zheng Y., Li L., Cai T. Cordyceps polysaccharide ameliorates airway inflammation in an ovalbumin- induced mouse model of asthma via TGF-β1/Smad signaling pathway. Respir. Physiol. Neurobiol. 2020;276:103412. doi: 10.1016/j.resp.2020.103412.
    1. Hosoi T., Ino S., Ohnishi F., Todoroki K., Yoshii M., Kakimoto M., Muller C.E., Ozawa K. Mechanisms of the action of adenine on anti-allergic effects in mast cells. Immun. Inflamm. Dis. 2018;6:97–105. doi: 10.1002/iid3.200.
    1. Hasko G., Cronstein B. Regulation of inflammation by adenosine. Front. Immunol. 2013;4:85. doi: 10.3389/fimmu.2013.00085.
    1. Yang X., Li Y., He Y., Li T., Wang W., Zhang J., Wei J., Deng Y., Lin R. Cordycepin alleviates airway hyperreactivity in a murine model of asthma by attenuating the inflammatory process. Int. Immunopharmacol. 2015;26:401–408. doi: 10.1016/j.intimp.2015.04.017.
    1. Carr V.M., Robinson A.M. Induction of allergic rhinitis in mice. Methods Mol. Biol. 2013;1032:145–158.
    1. Ko M.T., Huang S.C., Kang H.Y. Establishment and characterization of an experimental mouse model of allergic rhinitis. Eur. Arch. Otorhinolaryngol. 2015;272:1149–1155. doi: 10.1007/s00405-014-3176-2.
    1. McCusker C., Chicoine M., Hamid Q., Mazer B. Site-specific sensitization in a murine model of allergic rhinitis: Role of the upper airway in lower airways disease. J. Allergy Clin. Immunol. 2002;110:891–898. doi: 10.1067/mai.2002.130048.
    1. Hussain I., Randolph D., Brody S.L., Song S.K., Hsu A., Kahn A.M., Chaplin D.D., Hamilos D.L. Induction, distribution and modulation of upper airway allergic inflammation in mice. Clin. Exp. Allergy. 2001;31:1048–1059. doi: 10.1046/j.1365-2222.2001.01129.x.
    1. Cho S.H., Oh S.Y., Zhu Z., Lee J., Lane A.P. Spontaneous eosinophilic nasal inflammation in a genetically-mutant mouse: Comparative study with an allergic inflammation model. PLoS ONE. 2012;7:e35114. doi: 10.1371/journal.pone.0035114.
    1. Jung H.W., Jung J.K., Park Y.K. Antiallergic effect of Ostericum koreanum root extract on ovalbumin-induced allergic rhinitis mouse model and mast cells. Asian Pac J. Allergy Immunol. 2011;29:338–348.
    1. Meurer S.K., Ness M., Weiskirchen S., Kim P., Tag C.G., Kauffmann M., Huber M., Weiskirchen R. Isolation of Mature (Peritoneum-Derived) Mast Cells and Immature (Bone Marrow-Derived) Mast Cell Precursors from Mice. PLoS ONE. 2016;11:e0158104. doi: 10.1371/journal.pone.0158104.
    1. Gulledge T.V., Collette N.M., Mackey E., Johnstone S.E., Moazami Y., Todd D.A., Moeser A.J., Pierce J.G., Cech N.B., Laster S.M. Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide. J. Ethnopharmacol. 2018;212:166–174. doi: 10.1016/j.jep.2017.10.012.
    1. Kim S.H., Lee S., Kim I.K., Kwon T.K., Moon J.Y., Park W.H., Shin T.Y. Suppression of mast cell-mediated allergic reaction by Amomum xanthiodes. Food Chem. Toxicol. 2007;45:2138–2144. doi: 10.1016/j.fct.2007.05.011.
    1. Im S.J., Ahn M.H., Han I.H., Song H.O., Kim Y.S., Kim H.M., Ryu J.S. Histamine and TNF-alpha release by rat peritoneal mast cells stimulated with Trichomonas vaginalis. Parasite. 2011;18:49–55. doi: 10.1051/parasite/2011181049.
    1. Tiligada E., Aslanis D., Delitheos A., Varonos D. Changes in histamine content following pharmacologically-induced mast cell degranulation in the rat conjunctiva. Pharmacol. Res. 2000;41:667–670. doi: 10.1006/phrs.1999.0637.
    1. Han R.T., Kim S., Choi K., Jwa H., Lee J., Kim H.Y., Kim H.J., Kim H.R., Back S.K., Na H.S. Asthma-like airway inflammation and responses in a rat model of atopic dermatitis induced by neonatal capsaicin treatment. J. Asthma Allergy. 2017;10:181–189. doi: 10.2147/JAA.S124902.
    1. Thomsen J.S., Petersen M.B., Benfeldt E., Jensen S.B., Serup J. Scratch induction in the rat by intradermal serotonin: A model for pruritus. Acta Derm. Venereol. 2001;81:250–254. doi: 10.1080/00015550152572868.
    1. Sundaram A., Chen C., Khalifeh-Soltani A., Atakilit A., Ren X., Qiu W., Jo H., DeGrado W., Huang X., Sheppard D. Targeting integrin alpha5beta1 ameliorates severe airway hyperresponsiveness in experimental asthma. J. Clin. Investig. 2017;127:365–374. doi: 10.1172/JCI88555.
    1. Sakae R.S., Leme A.S., Dolhnikoff M., Pereira P.M., do Patrocinio M., Warth T.N., Zin W.A., Saldiva P.H., Martins M.A. Neonatal capsaicin treatment decreases airway and pulmonary tissue responsiveness to methacholine. Pt 1Am. J. Physiol. 1994;266:L23–L29. doi: 10.1152/ajplung.1994.266.1.L23.
    1. Whitehead G.S., Grasman K.A., Kimmel E.C. Lung function and airway inflammation in rats following exposure to combustion products of carbon-graphite/epoxy composite material: Comparison to a rodent model of acute lung injury. Toxicology. 2003;183:175–197. doi: 10.1016/S0300-483X(02)00542-5.
    1. Kuperman D.A., Huang X., Koth L.L., Chang G.H., Dolganov G.M., Zhu Z., Elias J.A., Sheppard D., Erle D.J. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 2002;8:885–889. doi: 10.1038/nm734.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe