Guifu Dihuang Pills Ameliorated Mucus Hypersecretion by Suppressing Muc5ac Expression and Inactivating the ERK-SP1 Pathway in Lipopolysaccharide/Cigarette Smoke-Induced Mice.

Huanhuan Zhang,Yusen Zhong,Yiyou Lin,Chenhuan Yu,Wenying Yu,Liting Ji,Changyu Li,Huazhong Ying,Vahideh Ghorani Sirjani

doi:10.1155/2021/9539218

Abstract

Mucus hypersecretion is a hallmark of chronic obstructive pulmonary disease (COPD) and is associated with increasing sputum production and declining pulmonary function. Therefore, reducing mucus secretion can be a new therapeutic opportunity for preventing COPD. The Guifu Dihuang pill (GFDHP) is a classical Chinese medicine and has been used as an immunoregulator for treatment of kidney yang deficiency syndrome, including hypothyroidism, adrenocortical hypofunction, chronic bronchitis, and COPD, for more than 2000 years. However, the protective effects and mechanisms of GFDHP against mucus hypersecretion in COPD remain obscure. The aim of the present study was to explore the inhibitory effects of GFDHP on lipopolysaccharide/cigarette smoke- (LPS/CS-) induced Mucin5ac (Muc5ac) overproduction and airway goblet cell hyperplasia in mice. The mice were randomly assigned into 6 groups: control, model, GFDHP-L, GFDHP-M, GFDHP-H, and dexamethasone. The mice were given LPS twice through intranasal inhalation and then exposed to CS daily for 6 weeks. Three doses of GFDHP were orally administered daily during the last 3 weeks of the experiment. Pulmonary function was examined with an EMKA pulmonary system, and pulmonary hyperpermeability and lung damage were evaluated with an in vivo imaging system. Inflammatory cells and cytokines in bronchoalveolar lavage fluid (BALF) were detected with a cell count analyzer and though ELISA analysis, respectively. Lung pathological changes and airway goblet cell hyperplasia were analyzed with hematoxylin and eosin and Alcian blue periodic acid Schiff staining. The protein expression levels of Muc5ac and extracellular signal-regulated kinase (ERK)-specificity protein1 (SP1) signaling pathway were measured with Western blot and immunohistochemistry. The results demonstrated that GFDHP improved pulmonary function and suppressed mouse pulmonary hyperpermeability and edema. GFDHP suppressed inflammatory cell infiltration and cytokine release in BALF, thereby elevating pulmonary function. It ameliorated lung pathological changes and airway goblet cell hyperplasia, and suppressed expression levels of Muc5ac mRNA and protein and phospho-ERK and SP1 levels in the lung tissues of the COPD mice. In conclusion, GFDHP inhibited mucus hypersecretion induced by LPS/CS by suppressing the activation of the ERK-SP1 pathway.

Highlights

As a worldwide burden, chronic obstructive pulmonary disease (COPD) affects more than 255 million people and has been one of the major causes of mortality and morbidity in smokers [1]
Apart from persistent airway inflammation and bronchial wall remodeling, goblet cells hyperplasia and mucus hypersecretion contribute to irreversible airflow limitation and pulmonary function deterioration [4]. erefore, reducing airway inflammatory response and suppressing mucus hypersecretion may be an effective approach for COPD treatment
To assess effects of Guifu Dihuang pill (GFDHP) on mouse pulmonary function, a noninvasive pneumotachograph was used in the mice of each group. e respiratory function parameters peak expiratory flow (PEF) and f decreased significantly compared with the control group, but the bronchial reactivity parameter PenH increased significantly in the model group (P < 0.05). ese results suggested lipopolysaccharide/ cigarette smoke- (LPS/cigarette smoking (CS)-)induced damage of the pulmonary function

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) affects more than 255 million people and has been one of the major causes of mortality and morbidity in smokers [1]. 8.6%, accounting for 99.9 million adults [2] It is a chronic progressive disease characterized by airflow limitation and persistent respiratory symptoms mainly caused by instance cigarette smoking (CS) or significant exposure to noxious particles or gases, which result in airway and/or alveolar abnormalities [3]. Apart from persistent airway inflammation and bronchial wall remodeling, goblet cells hyperplasia and mucus hypersecretion contribute to irreversible airflow limitation and pulmonary function deterioration [4]. Erefore, reducing airway inflammatory response and suppressing mucus hypersecretion may be an effective approach for COPD treatment Apart from persistent airway inflammation and bronchial wall remodeling, goblet cells hyperplasia and mucus hypersecretion contribute to irreversible airflow limitation and pulmonary function deterioration [4]. erefore, reducing airway inflammatory response and suppressing mucus hypersecretion may be an effective approach for COPD treatment

Methods

Results

Conclusion