The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Metformin alleviates chronic obstructive pulmonary disease and cigarette smoke extract-induced glucocorticoid resistance by activating the nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway

  • Tao, Fulin (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Zhou, Yuanyuan (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Wang, Mengwen (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Wang, Chongyang (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Zhu, Wentao (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Han, Zhili (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Sun, Nianxia (College of Pharmacy, Anhui University of Chinese Medicine) ;
  • Wang, Dianlei (College of Pharmacy, Anhui University of Chinese Medicine)
  • Received : 2021.08.02
  • Accepted : 2021.11.29
  • Published : 2022.03.01
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Abstract

Chronic obstructive pulmonary disease (COPD) is an important healthcare problem worldwide. Often, glucocorticoid (GC) resistance develops during COPD treatment. As a classic hypoglycemic drug, metformin (MET) can be used as a treatment strategy for COPD due to its anti-inflammatory and antioxidant effects, but its specific mechanism of action is not known. We aimed to clarify the role of MET on COPD and cigarette smoke extract (CSE)-induced GC resistance. Through establishment of a COPD model in rats, we found that MET could improve lung function, reduce pathological injury, as well as reduce the level of inflammation and oxidative stress in COPD, and upregulate expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), multidrug resistance protein 1 (MRP1), and histone deacetylase 2 (HDAC2). By establishing a model of GC resistance in human bronchial epithelial cells stimulated by CSE, we found that MET reduced secretion of interleukin-8, and could upregulate expression of Nrf2, HO-1, MRP1, and HDAC2. MET could also increase the inhibition of MRP1 efflux by MK571 significantly, and increase expression of HDAC2 mRNA and protein. In conclusion, MET may upregulate MRP1 expression by activating the Nrf2/HO-1 signaling pathway, and then regulate expression of HDAC2 protein to reduce GC resistance.

Keywords

Acknowledgement

This work was supported by grants from the National Natural Science Foundation of China (No. 81473536) and Anhui Provincial Natural Science Foundation (No. 2108085J45).

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