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ORIGINAL ARTICLE
Year : 2022  |  Volume : 17  |  Issue : 1  |  Page : 47-56

Histone deacetylase-2 inducer like theophylline has a potential to improve glucocorticoid responsiveness in severe uncontrolled asthma by reducing P-glycoprotein/MRP-1


1 Department of Biotechnology, Amity Institute of Biotechnology, Amity University, Lucknow Campus; Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Pulmonary Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Biotechnology, Amity Institute of Biotechnology, Amity University, Lucknow Campus, Lucknow, Uttar Pradesh, India
4 Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Correspondence Address:
Zia Hashim
Department of Pulmonary Medicine, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_85_21

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Background: Epigenetic factors play an essential role in regulating the action of steroids in asthma. Steroids suppress inflammation by recruiting histone deacetylase-2 (HDAC-2), which removes the acetyl group of the nuclear factor kappa B-enabled inflammatory gene complex and disables its action. P-glycoprotein (P-gp)/Multidrug resistance-associated protein 1 (MRP-1), the energy-dependent efflux pumps, reduces the bioavailability of steroids in the cell by pumping it out. The expression of P-gp/MRP-1 and HDAC-2 has been linked to regulating the action of steroids in asthma. Therefore, the use of HDAC-2 inducer like theophylline might improve asthma control by improving steroid responsiveness. Objective: HDAC-2 inducer, theophylline, can improve glucocorticoid responsiveness in severe uncontrolled asthma (UA). Materials and Methods: We classified subjects into severe UA (n = 7, age: 52.36 ± 11.94 years), controlled asthma (CA) (n = 23, age: 50.65 ± 16.11 years), and treatment-naïve patients (n = 10, age: 50.60 ± 14.38 years). Peripheral blood mononuclear cells (PBMCs) were isolated and treated with theophylline (1 μM) and Trichostatin-A (TSA) (0.8 μM) for 48 h, for induction/suppression of HDAC-2, respectively. The messenger RNA (mRNA) expression extracted from PBMCs was studied for HDAC-2and P-gp/MRP-1 by quantitative real-time polymerase chain reaction. Results: The mRNA expression of P-gp/MRP-1 was higher, whereas HDAC-2 mRNA levels were significantly lower in UA at baseline. Exposure to theophylline reduced mRNA expression of P-gp/MRP-1 (fold change: 2.57/2.15 in UA; 1.27/1.26 in CA, respectively, P < 0.0001), but the HDAC-2 mRNA expression increased (fold change: 5.56 in UA; 6.85 in CA, respectively, P < 0.0001). However, TSA treatment resulted in higher mRNA levels for P-gp/MRP-1 (fold change: 7.45/7.26 in UA; 3.34/3.29 in CA, respectively, P < 0.0001), whereas it significantly lowered expression for HDAC-2(fold change: 1.39 in UA; 2.46 in CA, respectively, P < 0.0001). Conclusion: HDAC-2 inducer theophylline has a potential to induce response against steroid resistance in severe UA.


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