Brg1 Promotes Airway Mucus Hypersecretion via IL-13 and the JAK1/2-STAT6 Signaling Pathway in Asthma

Backgroud: The chromatin remodeling factor Brg1 (Brahma-related gene 1) is an important nuclear protein that promotes the transcriptional activation or inhibition of target genes by regulating ATP hydrolysis to generate energy which rearranges the position of nucleosomes and the interaction of histone DNA. In this study, we explored the effect of Brg1 on airway mucus hypersecretion in asthma.Methods: Six-to-eight-week-old female wild-type C57BL/6 mice (wild-type, WT) and type II alveolar epithelial cells (AECIIs) specifically knockout Brg1 mice (Brg1fl/fl) were selected as the experimental subjects. The asthma group was established with house dust mite (HDM), and the control group was treated with normal saline (n=10). Wright's staining was used to detect inflammatory cells in bronchoalveolar lavage fluid (BALF). Invasive lung function was used to assess the airway compliance. Hematoxylin and eosin and periodic acid-schiff staining were used to detect mucus secretion. The virus was used to knock down the Brg1 gene in the bronchial epithelial cell line (16HBE) and stimulated with HDM. Immunohistochemistry was used to measure mucin glycoprotein 5AC (MUC5AC) protein expression in the airway epithelium and 16HBE cells. Western blotting was used to detect the expression of the MUC5AC and JAK1/2-STAT6 signaling pathways in mouse lung tissue and 16HBE. Co-immunoprecipitation (Co-IP) and Chromatin Immunoprecipitation (CHIP) were used to detect whether Brg1 could regulate the JAK1/2-STAT6 signaling pathway.Results: Specifically, knocking out the Brg1 gene in AECIIs can reduce airway inflammation, airway compliance, and mucus hypersecretion in asthma. Knockdown of the Brg1 gene can simultaneously reduce Interleukin-13 (IL-13) and the expression of MUC5AC protein in airway epithelial cells and the activation of the JAK1/2-STAT6 signaling pathway. The results of Co-IP and CHIP showed that Brg1 could bind to the JAK1/2 promoter region, regulating the activity of the JAK1/2-STAT6 pathway affects airway mucus secretion in asthma.Conclusion: Brg1 gene knockout in airway epithelial cells can reduce asthmatic airway mucus hypersecretion and the expression of MUC5AC protein in airway epithelial cells partly by inhibiting the activation of the JAK1/2-STAT6 signaling pathway.

Oncostatin M expression induced by bacterial triggers drives airway inflammatory and mucus secretion in severe asthma

Bacterial-associated LPS drives oncostatin M–dependent airway inflammation and mucus hypersecretion in severe asthma.

Reduction of Pulmonary Inflammation by pH Modifiers

Pulmonary inflammation is a common pathological feature of a variety of diseases, ofwhich successful therapy with currently available anti-inflammatory drugs is limited byresistance and adverse side effects. Using the ovalbumin-induced mouse allergic asthma model,the present study shows that treatments with pH modifiers, particularly simple acids such asacetate or hydrochloric acid, effectively depleted inflammatory cells in the lungs and blood aswell as hyperplastic lung tissue cells while preserving the structure of the blood vessels and lungparenchyma. The acid treatments also suppressed mucus hypersecretion. These resultsdemonstrated pH modifiers as a new class of broad-spectrum anti-inflammatory agents with antiproliferationand mucus suppression activities.

Reduction of Pulmonary Inflammation by pH Modifiers

Pulmonary inflammation is a common pathological feature of a variety of diseases, of which successful therapy with currently available anti-inflammatory drugs is limited by resistance and adverse side effects. Using the ovalbumin-induced mouse allergic asthma model, the present study shows that treatments with pH modifiers, particularly simple acids such as acetate or hydrochloric acid, effectively depleted inflammatory cells in the lungs and blood as well as hyperplastic lung tissue cells while preserving the structure of the blood vessels and lung parenchyma. The acid treatments also suppressed mucus hypersecretion. These results demonstrated pH modifiers as a new class of broad-spectrum anti-inflammatory agents with anti-proliferation and mucus suppression activities.

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

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.

Tiotropium Bromide Attenuates Mucus Hypersecretion in Patients with Stable Chronic Obstructive Pulmonary Disease

Background. Patients with stable chronic obstructive pulmonary disease (COPD) have been observed to benefit from tiotropium bromide. However, there are few studies of tiotropium bromide on sputum and sputum viscosity. To evaluate the effect of tiotropium bromide on mucus hypersecretion, a randomized, double-blind controlled trial was performed. Methods. 120 cases of patients with pulmonary function grade II were divided into two groups, which include the treatment group given tiotropium bromide powder inhalation (18 μg, inhalation, QD) and the control group given formoterol fumarate powder inhalation (12 μg, inhalation, BID) plus ambroxol hydrochloride tablets (60 mg, oral, TID). After 3 months of treatment, the pulmonary function and α1-acid glycoprotein (α1-AGP) in sputum were detected, and the changes of glycoprotein and Ca2+ content were evaluated by Miller classification. Results. Three patients (2 cases in the treatment group and 1 case in the control group) were dropped due to loss of follow-up, and 117 cases of patients were enrolled in this study. After 3 months of treatment, the sputum character score, α1-acid glycoprotein, Ca2+ content, and lung function of the two groups were significantly improved; group comparison analyses revealed that there was no significant difference in the content of α1-AGP, Ca2+ in sputum, and lung function between the two groups ( P > 0.05 ), but the improvement of sputum properties was significant ( P < 0.05 ), and the treatment group was better than the control group ( t = − 2.77 ; P = 0.007 ). Conclusions. Inhaled tiotropium bromide can effectively inhibit the mucus hypersecretion in stable COPD patients, improve the sputum properties and lung function of patients, and improve the quality of life of patients.

Abnormal Airway Mucus Secretion Induced by Virus Infection

The airway mucus barrier is a primary defensive layer at the airway surface. Mucins are the major structural components of airway mucus that protect the respiratory tract. Respiratory viruses invade human airways and often induce abnormal mucin overproduction and airway mucus secretion, leading to airway obstruction and disease. The mechanism underlying the virus-induced abnormal airway mucus secretion has not been fully studied so far. Understanding the mechanisms by which viruses induce airway mucus hypersecretion may open new avenues to treatment. In this article, we elaborate the clinical and experimental evidence that respiratory viruses cause abnormal airway mucus secretion, review the underlying mechanisms, and also discuss the current research advance as well as potential strategies to treat the abnormal airway mucus secretion caused by SARS-CoV-2.