Andrographolide Rescued Airway Epithelial E-Cadherin Redistribution in Toluene Diisocyanate-Induced Asthma
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1
Putra Malaysia University, Malaysia
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2
Bayero University Kano, Nigeria
Background: Exposure to toluene diisocyanate (TDI) induces oxidative stress, airway dysfunction and neutrophilic inflammation, leading to the pathogenesis of TDI-induced occupational asthma (TDI-OA). Evidence suggests that andrographolide (AGP) plays an important role in the management of eosinophilic asthma. Yet, its role in the control of TDI-induced E-cadherin redistribution and airway neutrophilia remain uncertain. This study evaluated the therapeutic potential of AGP in mouse model of TDI-OA.
Method: Female Balb/c mice were sensitised on day 1 and 8 by dermal injection of 0.3% TDI, while on day 15, 18 and 21 the animals were intranasally challenged with 0.1% TDI. Treatment was administered following a prophylactic regimen. 24 hours after the final exposure, bronchoalveolar lavage fluid (BALF), lung samples and serum were collected. The BALF was analysed for intracellular reactive oxygen species, total and differential leukocyte counts. Lung tissue inflammation, mucus production, collagen deposition and immunoreactivity of E-cadherin-β-catenin complexes were analysed. Airway hyperactivity was assessed by airway hyperresponsiveness test. Genetic expression of Th2/Th1 cytokines, markers of airway remodelling and oxidative stress were evaluated by qPCR.
Results: Total number of cells in the BALF of treated mice was significantly higher than in control mice. Treatment with AGP dose-dependently decreased TDI-induced airway neutrophilia. Similarly, lung tissue inflammatory cell infiltrates, mucus production and collagen deposition were significantly decreased by AGP. Induction of aberrant distribution of E-cadherin-β-catenin complexes was observed upon TDI exposure. AGP restored normal distribution of E-cadherin-β-catenin complexes, thereby reviving airway integrity. The prevention of aberrant E-cadherin-β-catenin complex distribution occurred possibly via AGP-mediated increase in p38 phosphorylation, Nrf2 activation and HO-1 production. Furthermore, AGP upregulated Nrf2 and HO-1 expressions.
Conclusion: These findings suggest that AGP attenuated TDI-OA by preventing TDI-induced aberrant E-cadherin distribution through the restoration of epithelial β-catenin and activation of p38-dependent Nrf2 induction.
Acknowledgements
This work was funded by National Key Economic Area Research Grant Scheme (NRGS), provided by the Ministry of Agriculture and Agro-Based Industry, Malaysia (NRGS/NH1014D026).
References
Yao L, Zhao H, Tang H, Song J, Dong H, Zou F, et al. Phosphatidylinositol 3-kinase mediates β-catenin dysfunction of airway epithelium in a toluene diisocyanate-induced murine asthma model. Toxicological Sciences. 2015;147(1):168–77.
Kim SH, Choi GS, Ye YM, Jou I, Park HS, Park SM. Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: Implications for toluene diisocyanate-induced asthma. Clinical and Experimental Immunology. 2010;160(3):489–97.
Keywords:
Asthma,
Andrographolide (AGP),
E-cadherin (E-CAD),
Toluene diisocyanate (TDI),
Nrf 2
Conference:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019.
Presentation Type:
Oral Presentation
Topic:
Inflammatory diseases
Citation:
Sulaiman
I,
Lim
CJ,
Mohtaruddin
N and
Stanslas
J
(2019). Andrographolide Rescued Airway Epithelial E-Cadherin Redistribution in Toluene Diisocyanate-Induced Asthma.
Front. Pharmacol.
Conference Abstract:
International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18)
“Seizing Opportunities and Addressing Challenges of Precision Medicine”.
doi: 10.3389/conf.fphar.2019.63.00020
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Received:
07 Nov 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Dr. Ibrahim Sulaiman, Putra Malaysia University, Seri Kembangan, Malaysia, ibrahimbnsulayman@yahoo.com