Skip to main content

Advertisement

SpringerLink
Log in

Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Objective

Bacterial infections can exacerbate asthmatic inflammation depending on lipopolysaccharide (LPS) composition, the outermost component of cell wall, its exposure timings as well as host’s immune status. In present study, Balb/c mice were exposed to antigen (ovalbumin) and LPS simultaneously to establish an asthmatic model. Curcumin (diferuloylmethane), well known for its anti-inflammatory potential, was administered through intranasal route 1 h before LPS and OVA (ovalbumin) exposure to evaluate its efficacy against airway structural changes.

Methods

Inflammatory cell infiltration in lungs was measured by flow cytometry and further eosinophils were especially measured by immunofluorescence detection of major basic protein (MBP) as marker of eosinophilc granule protein. We also measured reactive oxygen species (ROS) in BALF by spectrofluorometry. MMP-9 activity was evaluated by gelatin zymography and mRNA expressions of MMP-9, TIMP-1, TGF-β1, IL-13, Collagen-1 and TLR-4 were measured in lungs. Protein expression of MAP kinases (P-ERK, P-JNK, P-p38), TLR-4, Cox-2, Lox-5 and Eotaxin was measured by western blotting. Hydroxyproline level and masson’s trichrome staining were used to evaluate collagen deposition in lung.

Results

Exposure to LPS (0.1 µg) exacerbates airway inflammation and induces structural changes in lungs by enhanced ROS production, collagen deposition, expression of genes involved in airway remodeling and activation of MAP kinases pathway enzymes. Intranasal curcumin pretreatment had significantly suppressed inflammatory mediators and airway remodeling proteins.

Conclusion

Our results strongly suggest that intranasal curcumin effectively protects LPS-induced airway inflammation and structural changes by modulating genes involved in airway remodeling in safer way; hence, it can be considered as supplementary alternative towards asthma treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  • Al-Alawi M, Hassan T, Chotirmall SH (2014) Transforming growth factor β and severe asthma: a perfect storm. Respir Med 108:1409–1423

    Article  PubMed  Google Scholar 

  • Alam R, Gorska MM (2011) Mitogen-activated protein kinase signaling and ERK1/2 bistability in asthma. Clin Exp Allergy 41:149–159

    Article  CAS  PubMed  Google Scholar 

  • Arima M, Fukuda T (2011) Prostaglandin D2 and TH2 inflammation in the pathogenesis of bronchial asthma. Korean J Intern Med 26:1–8

    Article  CAS  Google Scholar 

  • Belleguic C, Corbel M, Germain N, Lena H, Boichot E, Delaval PH, Lagente V (2002) Increased release of matrix metalloproteinase-9 in the plasma of acute severe asthmatic patients. Clin Exp Allergy 32:217–223

    Article  CAS  PubMed  Google Scholar 

  • Bergeron C, Al-Ramli W, Hamid Q (2009) Remodeling in asthma. Am Thorac Soc 6:301–305

    Article  Google Scholar 

  • Bottcher MF, Hmani-Aifa M, Lindstrom A, Jenmalm MC, Mai XM, Nilsson L, Zdolsek HA, Bjorksten B, Soderkvist P, Vaarala O (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12 (p70) responses in Swedish children. J Allergy Clin Immunol 114:561–567

    Article  CAS  Google Scholar 

  • Caramori G, Papi A (2004) Oxidants and asthma. Thorax 59:170–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chauhan PS, Dash D, Singh R (2014) Intranasal curcumin attenuates airway remodeling in murine model of chronic asthma. Int Immunopharmacol 21:63–75

    Article  CAS  PubMed  Google Scholar 

  • Chopra P, Kanoje V, Semwal A, Ray A (2008) Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases. Expert Opin Investig Drugs 17:1411–1425

    Article  CAS  PubMed  Google Scholar 

  • Choudhury BK, Wild JS, Alam R, Klinman DM, Boldogh I, Dharajiya N, Mileski WJ, Sur S (2002) In vivo role of p38 mitogen-activated protein kinase in mediating the anti-inflammatory effects of CpG oligodeoxynucleotide in murine asthma. J Immunol 169:5955–5961

    Article  CAS  PubMed  Google Scholar 

  • Claar D, Hartert TV, Peebles RS Jr (2015) The role of prostaglandins in allergic lung inflammation and asthma. Expert Rev Respir Med 9:55–72

    Article  CAS  PubMed  Google Scholar 

  • Conroy DM, Williams TJ (2001) Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir Res 2:150–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Danahay H, Atherton H, Jones G, Bridges RJ, Poll CT (2002) Interleukin-13 induces a hypersecretory ion transport phenotype in human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 282:226–236

    Article  Google Scholar 

  • Dong L, Li H, Wang S, Li Y (2009) Different doses of lipopolysaccharides regulate the lung inflammation of asthmatic mice via TLR4 pathway in alveolar macrophages. J Asthma 46:229–233

    Article  CAS  PubMed  Google Scholar 

  • Doreswamy V, Alexis NE, Zhou H, Peden DB (2011) Nasal PMN response to repeated challenge with endotoxin in healthy volunteers. Inhal Toxicol 23:142–147

    Article  CAS  PubMed  Google Scholar 

  • Douwes J, Gibson P, Pekkanen J, Pearce N (2002) Non-eosinophilic asthma: importance and possible mechanisms. Thorax 57:643–648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eruslanov E, Kusmartsev S (2010) Identification of ROS using oxidized DCFDA and flow-cytometry. Adv Protoc Oxidative Stress 594:57–72

    Article  CAS  Google Scholar 

  • Fulkerson PC, Fischetti CA, McBride ML, Hassman LM, Hogan SP, Rothenberg ME (2006) A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation. Proc Natl Acad Sci 103:16418–16423

    Article  CAS  PubMed  Google Scholar 

  • Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID (2002) Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 57:875–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gundel RH, Letts LG, Gleich GJ (1991) Human eosinophil major basic protein induces airway constriction and airway hyperresponsiveness in primates. J Clin Invest 87:1470–1473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JS, Kang JY, Ha JH, Lee HY, Kim SJ, Kim SC, Ahn JH, Kwon SS, Kim YK, Lee SY (2013) Expression of nerve growth factor and matrix metallopeptidase-9/tissue inhibitor of metalloproteinase-1 in asthmatic patients. J Asthma 50:712–717

    Article  CAS  PubMed  Google Scholar 

  • Kumari A, Dash D, Singh R (2015) Lipopolysaccharide (LPS) exposure differently affects allergic asthma exacerbations and its amelioration by intranasal curcumin in mice. Cytokine 76:334–342

    Article  CAS  PubMed  Google Scholar 

  • Kumari A, Dash D, Singh R (2017) Curcumin inhibits lipopolysaccharide (LPS)-induced endotoxemia and airway inflammation through modulation of sequential release of inflammatory mediators (TNF-α and TGF-β1) in murine model. Inflammopharmacology 25:329–341

    Article  CAS  PubMed  Google Scholar 

  • Kupai K (2011) Gelatin zymography for detection of matrixmetalloproteinase-2 and-9 (MMP-2, MMP-9) from myocardium samples. In a practical manual p 29

  • Lloyd CM, Hawrylowicz CM (2009) Regulatory T cells in asthma. Immunity 31:438–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  Google Scholar 

  • Makinde T, Murphy RF, Aggarwal DK (2007) The regulatory role of TGF-β in airway remodeling in asthma. Immunol Cell Biol 2007:85–348

    Google Scholar 

  • Martel-Pelletier J, Lajeunesse D, Reboul P, Pelletier JP (2003) Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs. Ann Rheum Dis 62:501–509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McBrien CN, Menzies-Gow A (2017) The biology of eosinophils and their role in asthma. Front Med 4:93

    Article  Google Scholar 

  • Mohamed GM, Farres MN, Mahmoud H (2012) Interplay between matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in acute asthma exacerbation and airway remodeling. Egypt J Chest Dis Tuberc 61:35–39

    Article  Google Scholar 

  • Munitz A, Brandt EB, Mingler M, Finkelman FD, Rothenberg ME (2008) Distinct roles for IL-13 and IL-4 via IL-13 receptor α1 and the type II IL-4 receptor in asthma pathogenesis. Proc Natl Acad Sci 105:7240–7245

    Article  PubMed  Google Scholar 

  • Nelson HS, Davies DE, Wicks J, Powell RM, Puddicombe SM, Holgate ST (2003) Airway remodeling in asthma: new insights. J Allergy Clin Immunol 111:215–225

    Article  CAS  Google Scholar 

  • Ohbayashi H, Shimokata K (2005) Matrix metalloproteinase-9 and airway remodeling in asthma. Curr Drug Targets Inflamm Allergy 4:177–181

    Article  CAS  PubMed  Google Scholar 

  • Oshita Y, KogaT Kamimura T, Matsuo K, Rikimaru T, Aizawa H (2003) Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma. Thorax 58:757–760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peebles RS, Sheller JR (2002) Role of prostaglandins in asthma. Immunol Allergy Clin 22:827–844

    Article  Google Scholar 

  • Perros F, Lambrecht BN, Hammad H (2011) TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways. Respir Res 12:125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roland NJ, Bhalla RK, Earis J (2004) The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest 126:213–219

    Article  CAS  PubMed  Google Scholar 

  • Sackesen C, Karaaslan C, Keskin O, Tokol N, Tahan F, Civelek E, Soyer OU, Adalıoglu G, Uncer A, Birben E, Oner C (2005) The effect of polymorphisms at the CD14 promoter and the TLR4 gene on asthma phenotypes in Turkish children with asthma. Allergy 60:1485–1492

    Article  CAS  PubMed  Google Scholar 

  • Shim JJ, Dabbagh K, Ueki IF, Dao-Pick T, Burgel PR, Takeyama K, Tam DCW, Nadel JA (2001) IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am J Physiol Lung Cell Mol Physiol 280:134–140

    Article  Google Scholar 

  • Stelts D, Egan RW, Falcone A, Garlisi CG, Gleich GJ, Kreutner W, Kung TT, Nahrebne DK, Chapman RW, Minnicozzi M (1998) Eosinophils retain their granule major basic protein in a murine model of allergic pulmonary inflammation. Am J Respir Cell Mol Biol 18:463–470

    Article  CAS  PubMed  Google Scholar 

  • Sumi Y, Hamid Q (2007) Airway remodeling in asthma. Allergol Int 56:341–348

    Article  CAS  PubMed  Google Scholar 

  • Sutherland ER, Martin RJ (2007) Asthma and atypical bacterial infection. Chest 132:1962–1966

    Article  CAS  PubMed  Google Scholar 

  • Xue-Xi Y, Fen-Xia L, Wu YS, Wu D, Jia-Yu T, Li M (2011) Association of TGF-[beta] 1, IL-4 and IL-13 gene polymorphisms with asthma in a Chinese population. Asian Pac J Allergy Immunol 29:273

    Google Scholar 

  • Yang J, Li Q, Zhou XD, Kolosov VP, Perelman JM (2011) Naringenin attenuates mucous hypersecretion by modulating reactive oxygen species production and inhibiting NF-κB activity via EGFR-PI3 K-Akt/ERK MAP kinase signaling in human airway epithelial cells. Mol Cell Biochem 351:29–40

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Kim SC, Yu T, Yi YS, Rhee MH, Sung GH, Yoo BC, Cho JY (2014) Functional roles of p38 mitogen-activated protein kinase in macrophage-mediated inflammatory responses. Mediat Inflamm 20:2014

    Google Scholar 

  • Zhu HT, Bian C, Yuan JC, Chu WH, Xiang X, Chen F, Wang CS, Feng H, Lin JK (2014) Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J neuroinflamm 11:59

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Department of Science and Technology-Science and Engineering Research Board, New Delhi, India (DST-SERB). Real time PCR (ABI 7500) and flow cytometer (FACS Calibur, BD Biosciences) studies were performed at Central facility of Interdisciplinary Institute of Life Sciences (ISLS), Banaras Hindu University, Varanasi India.

Author information

Authors and Affiliations

  1. Department of Zoology, MMV, Banaras Hindu University, Varanasi, 221005, India

    Asha Kumari & Rashmi Singh

  2. Department of Physics, Udai Pratap Autonomous College, Varanasi, India

    D. K. Singh

  3. Department of Biochemistry, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, India

    D. Dash

Authors
  1. Asha Kumari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Dash
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rashmi Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rashmi Singh.

Ethics declarations

Conflict of interest

Authors have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kumari, A., Singh, D.K., Dash, D. et al. Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model. Inflammopharmacol 27, 731–748 (2019). https://doi.org/10.1007/s10787-018-0544-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-018-0544-3

Keywords

Search

Navigation