Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways. Its main pathological manifestations include airway inflammation, mucus hypersecretion, oxidative stress and apoptotic epithelial cells. Recent research suggests that MAP kinases and Keap1-Nrf2-ARE signaling pathway are involved in the pathological process of inflammation and oxidative stress. This review explores the potential role of the cross talk of these signaling pathways in airway inflammation, mucus hypersecretion, oxidative stress and apoptotic epithelial cells. To clarify the roles of cross talk between MAP kinases and Keap1-Nrf2-ARE signaling pathway, we also focus on the drugs related to that in the treatment of COPD, and it provides ideas for more drug research in the treatment of COPD.

Objective To study the impact of establishment of lipopolysaccharide ( LPS )-induced rat model of chronic obstructive pulmonary disease (COPD)on the function of multidrug resistance-associated protein 1(MRP1)in the rat bronchial epithelium .Methods Using intratracheal instillation of LPS to establish COPD rat model .8-week old healthy male Wistar rats were divided into 3 groups (10 rats in each group ):(1) Normal control;(2) Modeling for 14 days after LPS instillation;(3) Modeling for 28 days after LPS instillation.Pulmonary function and the concentration of phenol red in bronchoalveolar lavage fluid ( BALF) and plasma were measured .The ratio of phenol red concentration in BALF/plasma was used as an index of the MRP 1 function in the rat bronchial epithelium and the expression of MRP 1 in the bronchial epi-thelium was also observed by immunohistochemistry .Results Compared with the normal group , the pulmonary functions of the rats in the model groups were significantly reduced along with the modeling progress .After intravenous administration of phenol red, the ratio of phenol red concentration in BALF/plasma was gradually reduced , and the expression of MRP1 in the bronchial epithelium was significantly decreased .Conclusions COPD rat model can be established by intratracheal LPS instillation, and the function of MRP1 in bronchial epithelium was gradually reduced along with the modeling progress .

Aim To develop a HPLC method for the determination of the concentration of 1,8-TMP rhein in rat plasma and study the pharmacokinetics of 1,8-TMP rhein in rat plasma after single dose i. v. administration of 1,8-TMP rhein (2, 4, 8 mg·kg - 1 ). Methods Emodin was used as an internal standard. Plasma sam-ples were extracted with methanol and analyzed by HPLC. The mobile phase was methanol - 0. 1% for-mic acid water (78 ∶ 22, V/ V), with a flow rate of 1. 0 mL·min - 1 and UV 275 nm as the detection wave-length. The plasma concentration of 1,8-TMP rhein in rats was determined by HPLC after single-dose intrave-nous injection in rats with 2,4 and 8 mg·kg - 1 of 1,8-TMP rhein, and the pharmacokinetic parameters were caclulated by DAS 2. 1. Results The result of cali-bration curve was linear over the range of 0. 05 ~ 10. 00 mg·L - 1 (r = 0. 996 2). The lower limit of quantifica-tion was 0. 05 mg · L - 1 . The intra-day and inter-day precision (RSD% ) were both lower than 6% , and the extraction recoveries were higher than 88% , respec-tively. The validated method was successfully applied to a pharmacokinetic study after i. v. administration of 1,8-TMP rhein in rats with a dose of 2,4 and 8 mg· kg - 1 . The T1 / 2 was (68. 35 ± 1. 36), (69. 32 ± 2. 1) and (69. 32 ± 2. 03) min, respectively. The AUC0 - t was ( 101. 03 ± 24. 90 ), ( 144. 79 ± 3. 29 ) and (231. 92 ± 19. 30 ) min · mg · L - 1 , respectively. Conclusion A simple and specific HPLC method for the analysis of 1,8-TMP rhein is successfully developed and applied to a pharmacokinetic study in rat plasma.

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.

The present study aimed to examine the effect of allyl isothiocyanate (AITC) on chronic obstructive pulmonary disease and to investigate whether upregulation of multidrug resistance-associated protein 1 (MRP1) associated with the activation of the PARK7 (DJ-1)uclear factor erythroid 2-related factor 2 (Nrf2) axis.Lung function indexes and histopathological changes in mice were assessed by lung function detection and H&E staining. The expression levels of Nrf2, MRP1, heme oxygenase-1 (HO-1), and DJ-1 were determined by immunohistochemistry, Western blotting and reverse transcription-quantitative polymerase chain reaction. Next, the expression of DJ-1 in human bronchial epithelial (16HBE) cells was silenced by siRNA, and the effect of DJ-1 expression level on cigarette smoke extract (CSE)-stimulated protein degradation and AITC-induced protein expression was examined. The expression of DJ-1, Nrf2, HO-1, and MRP1 was significantly decreased in the wild type model group, while the expression of each protein was significantly increased after administration of AITC. Silencing the expression of DJ-1 in 16HBE cells accelerated CSE-induced protein degradation, and significantly attenuated the AITC-induced mRNA and protein expression of Nrf2 and MRP1. The present study describes a novel mechanism by which AITC induces MRP1 expression by protecting against CS/CSEmediated DJ-1 protein degradation via activation of the DJ-1/Nrf2 axis.

The present study aimed to examine the effect of allyl isothiocyanate (AITC) on chronic obstructive pulmonary disease and to investigate whether upregulation of multidrug resistance-associated protein 1 (MRP1) associated with the activation of the PARK7 (DJ-1)uclear factor erythroid 2-related factor 2 (Nrf2) axis.Lung function indexes and histopathological changes in mice were assessed by lung function detection and H&E staining. The expression levels of Nrf2, MRP1, heme oxygenase-1 (HO-1), and DJ-1 were determined by immunohistochemistry, Western blotting and reverse transcription-quantitative polymerase chain reaction. Next, the expression of DJ-1 in human bronchial epithelial (16HBE) cells was silenced by siRNA, and the effect of DJ-1 expression level on cigarette smoke extract (CSE)-stimulated protein degradation and AITC-induced protein expression was examined. The expression of DJ-1, Nrf2, HO-1, and MRP1 was significantly decreased in the wild type model group, while the expression of each protein was significantly increased after administration of AITC. Silencing the expression of DJ-1 in 16HBE cells accelerated CSE-induced protein degradation, and significantly attenuated the AITC-induced mRNA and protein expression of Nrf2 and MRP1. The present study describes a novel mechanism by which AITC induces MRP1 expression by protecting against CS/CSEmediated DJ-1 protein degradation via activation of the DJ-1/Nrf2 axis.

AIM: To explore the effect of Huatanjiangqi capsule medicated serum (HTJQ) on the resistance of human bronchial epithelial cells (16HBE) to glucocorticoid (GC) stimulated by cigarette smoke extract (CSE). METHODS: After 16HBE cells were treated with HTJQ, the effects of different concentrations of HTJQ on the viability of 16HBE cells were determined by CCK-8 method. 16HBE cells were pretreated with HTJQ, and then cultured with dexamethasone (DEX) and lipopolysaccharide (LPS) for 24 hours, the effect of HTJQ on glucocorticoid (GC) resistance of 16HBE cells was determined by Enzyme-linked immunosorbent assay (ELISA). The effects of HTJQ, sulforaphane (SFN) and glutathione (GSH) on the expression of NF-E2-related factors 2 (Nrf2), Heme oxygenase-1 (HO-1) and histone deacetylase 2 (HDAC2) in 16HBE cells stimulated by CSE were measured by Western blot, and the effects of HTJQ, SFN and GSH on interleukin-8 (IL-8) in 16HBE cells were measured by ELISA. RESULTS: HTJQ promoted the proliferation of 16HBE cells at 1 h, 2 h and 4 h, the results of ELISA and Western blot showed that CSE induced GC resistance and decreased the expression of Nrf2, HO-1 and HDAC2 in 16HBE cells, HTJQ significantly decreased IL-8 and improved GC sensitivity of 16HBE cells (P<0.01), and up-regulated the expression of Nrf2, HO-1 and HDAC2 (P<0.01). In addition, HTJQ significantly up-regulated the level of GSH in 16HBE cells (P<0.01). Nrf2 agonists SFN and GSH significantly improved the glucocorticoid sensitivity of 16HBE cells (P<0.01), and up-regulated the expression of Nrf2, HO-1 and HDAC2 (P<0.01). CONCLUSION: HTJQ improves the GC resistance of 16HBE cells by up-regulating the expression of Nrf2/HDAC2 protein and the level of intracellular GSH.