Abstract
Progression of chronic obstructive pulmonary disease is associated with small airway obstruction by accumulation of inflammatory mucous exudates. However, the mechanism of mucin hypersecretion after exposure to cigarette smoke (CS) is still not clear. In this study, we explored the contribution of β2-adrenoceptor (β2-AR) signaling to CS extract (CSE)-induced mucus hypersecretion in vitro and examined the effect of a β-blocker on airway mucin hypersecretion in vivo. NCI-H292 epithelial cell line was used to determine the contribution of β2-AR signaling to CSE-induced MUC5AC production by treatment with β2-AR antagonists propranolol and ICI118551 and β2-AR-targeted small interfering RNA. The effect of propranolol on airway mucus hypersecretion was examined in a rat model exposed to CS. MUC5AC expression was assayed by real-time PCR, immunohistochemistry and ELISA. β2-AR and its downstream signaling were detected by western blot analysis. We found that pretreating NCI-H292 cells with propranolol, ICI118551 for 30 min or β2AR–targeted siRNA for 48 h reduced MUC5AC mRNA and protein levels stimulated by CSE. However,inhibiting the classical β2AR–cAMP-PKA pathway didn’t attenuate CSE-induced MUC5AC production, while silencing β-arretin2 expression significantly decreased ERK and p38MAPK phosphorylation, thus reduced the CSE-stimulated MUC5AC production. In vivo, we found that administration of propranolol (25 mg kg−1d−1) for 28 days significantly attenuated the airway goblet cell metaplasia, mucus hypersecretion and MUC5AC expression of rats exposed to CS. From the study, β2-AR–β-arrestin2–ERK1/2 signaling was required for CS-induced airway MUC5AC expression. Chronic propranolol administration ameliorated airway mucus hypersecretion and MUC5AC expression in smoking rats. The exploration of these mechanisms may contribute to the optimization of β2-AR target therapy in chronic obstructive pulmonary disease.
Highlights
The normal mammalian airway epithelium produces and is coated by mucins such as MUC5B and MUC5AC, which protect the airway epithelia against exogenous insult
We previously showed that chronic exposure to propranolol, a nonselective b-AR antagonist, had a protective effect on airway smooth muscle contraction in rats exposed to cigarette smoke (CS) [12]
We further examined the effect of chronic propranolol administration on MUC5AC production in rats exposed to CS
Summary
The normal mammalian airway epithelium produces and is coated by mucins such as MUC5B and MUC5AC, which protect the airway epithelia against exogenous insult. B2-AR signaling has been proven to be required for the full development of 3 cardinal features of asthma: mucous hypersecretion, airway hyperresponsiveness and the presence of inflammatory cells in the lungs and chronic administration of ICI118551 or nadolol reduced inflammation and mucous metaplasia, that may contribute to airflow obstruction and airway hyperresponsiveness of asthma[7,9]. This evidence indicates b2AR is involved in regulating lung inflammation and mucus secretion. We further examined the effect of chronic propranolol administration on MUC5AC production in rats exposed to CS
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