T Xie1, Gy Luo2, Y Zhang1, X Wang1, Xy Wang1, M Wu3, Gp Li1,4. 1. Inflammations & Allergic Diseases Research Unit, First Affiliated Hospital of Sichuan Medical University, Luzhou, Sichuan, China. 2. Staff Health Clinic, Sichuan Medical University, Luzhou, Sichuan, China. 3. Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA. 4. State Key Laboratory of Respiratory Disease for Allergy, School of Medicine, Shenzhen University, Shenzhen, Guangdong, China.
Abstract
BACKGROUND: Airway mucus hypersecretion is a key pathophysiological feature in asthma. Fasudil, a selective Rho-A/Rho kinase inhibitor, has been used in clinical trials to treat pulmonary hypertension. However, its function in modulating airway mucus hypersecretion in asthma remains undefined. OBJECTIVE: We examined whether fasudil, a selective Rho-A/Rho kinase inhibitor, affects the mucus hypersecretion by suppressing MUC5AC via signal transducer and activator of transcription factor 6 (STAT6) and nuclear factor-kappa B (NFκB) in mice and cells. METHODS: We measured mucus secretion and the expression of Rho-kinase in the airway tissue of patients with asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA) followed with fasudil treatment. The lung tissues were assessed for airway inflammation and mucus secretion. Cytokine levels and airway responsiveness were determined. STAT6 and NFκB were quantified by Western blot. 16HBE cells were stimulated with house dust mite (HDM) extracts. MUC5AC and muc5ac promoter activities were measured. Using siRNA to knockdown STAT6 in epithelial cells, we determined the impact of STAT6 on muc5ac promoter activity. NFκB nuclear translocation was observed with immunostaining. RESULTS: Fasudil administration significantly decreased the number of inflammatory cells, inflammation index in the lung and airway responsiveness. Fasudil also reduced mucous secretion and MUC5AC expression in OVA-challenged mice. Fasudil down-regulated the levels of IL-17, IL-4 and IL-13 in the lung tissue of OVA-challenged mice. Fasudil also decreased the expression and phosphorylation of NFκB and STAT6 as well as the nuclear translocation of NFκB. In addition, human airway epithelial cells (16HBE) were challenged with HDM extracts and then treated with fasudil. Fasudil inhibited HDM extract-induced MUC5AC expression, which is associated with a reduction in STAT6 and NFκB in epithelial cells. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that the Rho-A/Rho kinase inhibitor, fasudil, plays a negative regulatory role in allergen-induced mucus secretion and MUC5AC expression by regulating STAT6 and NFκB.
BACKGROUND: Airway mucus hypersecretion is a key pathophysiological feature in asthma. Fasudil, a selective Rho-A/Rho kinase inhibitor, has been used in clinical trials to treat pulmonary hypertension. However, its function in modulating airway mucus hypersecretion in asthma remains undefined. OBJECTIVE: We examined whether fasudil, a selective Rho-A/Rho kinase inhibitor, affects the mucus hypersecretion by suppressing MUC5AC via signal transducer and activator of transcription factor 6 (STAT6) and nuclear factor-kappa B (NFκB) in mice and cells. METHODS: We measured mucus secretion and the expression of Rho-kinase in the airway tissue of patients with asthma. BALB/c mice were sensitized and challenged with ovalbumin (OVA) followed with fasudil treatment. The lung tissues were assessed for airway inflammation and mucus secretion. Cytokine levels and airway responsiveness were determined. STAT6 and NFκB were quantified by Western blot. 16HBE cells were stimulated with house dust mite (HDM) extracts. MUC5AC and muc5ac promoter activities were measured. Using siRNA to knockdown STAT6 in epithelial cells, we determined the impact of STAT6 on muc5ac promoter activity. NFκB nuclear translocation was observed with immunostaining. RESULTS:Fasudil administration significantly decreased the number of inflammatory cells, inflammation index in the lung and airway responsiveness. Fasudil also reduced mucous secretion and MUC5AC expression in OVA-challenged mice. Fasudil down-regulated the levels of IL-17, IL-4 and IL-13 in the lung tissue of OVA-challenged mice. Fasudil also decreased the expression and phosphorylation of NFκB and STAT6 as well as the nuclear translocation of NFκB. In addition, human airway epithelial cells (16HBE) were challenged with HDM extracts and then treated with fasudil. Fasudil inhibited HDM extract-induced MUC5AC expression, which is associated with a reduction in STAT6 and NFκB in epithelial cells. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that the Rho-A/Rho kinase inhibitor, fasudil, plays a negative regulatory role in allergen-induced mucus secretion and MUC5AC expression by regulating STAT6 and NFκB.
Authors: Collin G Johnson; Vandy P Stober; Jaime M Cyphert-Daly; Carol S Trempus; Gordon P Flake; Valbona Cali; Israr Ahmad; Ronald J Midura; Mark A Aronica; Sadis Matalon; Stavros Garantziotis Journal: Am J Physiol Lung Cell Mol Physiol Date: 2018-09-06 Impact factor: 5.464
Authors: Diego A Rojas; Pablo A Iturra; Andrea Méndez; Carolina A Ponce; Rebeca Bustamante; Miriam Gallo; Pamela Bórquez; Sergio L Vargas Journal: Sci Rep Date: 2019-02-14 Impact factor: 4.379