Abstract
Airway mucus overproduction is one of the most common symptoms of asthma that causes severe clinical outcomes in patients. Despite the effectiveness of general asthma therapies, specific treatments that prevent mucus overproduction in asthma patients remain lacking. Recent studies have found that activation of GABAA receptors (GABAAR) is important for promoting mucus oversecretion in lung airway epithelia. Here, we report that luteolin, a natural flavonoid compound, suppresses mucus overproduction by functionally inhibiting the GABAergic system. This hypothesis was investigated by testing the effects of luteolin on goblet cell hyperplasia, excessive mucus secretion, and GABAergic transmission using histological and electrophysiological approaches. Our results showed that 10 mg/kg luteolin significantly decreased the number of goblet cells in the lung tissue and inhibited mucus overproduction in an in vivo asthma model induced by ovalbumin (OVA) in mice. Patch-clamp recordings showed that luteolin inhibited GABAAR-mediated currents in A549 cells. Furthermore, the inhibitory effects of luteolin on OVA-induced goblet cell hyperplasia and mucus overproduction were occluded by the GABAAR antagonist picrotoxin. In conclusion, our observations indicate that luteolin effectively attenuates mucus overproduction at least partially by inhibiting GABAARs, suggesting the potential for therapeutic administration of luteolin in the treatment of mucus overproduction in asthma patients.
Highlights
Asthma is a major public health issue that affects as many as 300 million people worldwide, with a global prevalence ranging from 1% to 21% in adults; up to 20% of children aged 6 to 7 years old experience severe wheezing episodes within a year[1,2,3]
We found that luteolin (3′,4′,5,7-tetrahydroxyflavone), a natural flavonoid found in Perilla frutescens and many other medical herbs[23,24,25], directly inhibits GABAA receptors (GABAAR)-mediated current responses in lung epithelial cells (A549)
Treatment with different concentrations of luteolin inhibited gamma-aminobutyric acid (GABA) (2.5 μM)-induced currents in a dose-dependent manner, with an IC50 of 8.2 μM(Fig. 5B). These results suggest that luteolin directly targets GABAARs and inhibits their functions in human alveolar basal epithelial cells
Summary
Asthma is a major public health issue that affects as many as 300 million people worldwide (of all ages), with a global prevalence ranging from 1% to 21% in adults; up to 20% of children aged 6 to 7 years old experience severe wheezing episodes within a year[1,2,3]. Mucus overproduction is one of the most important pathological features of chronic inflammatory airway diseases that contribute to the morbidity and mortality associated with asthma, chronic obstructive pulmonary disease, and cystic fibrosis[7,8,9]. Mucus overproduction is characterized by enhanced mucin gene expression and mucin synthesis, excessive mucus secretion, goblet cell hyperplasia, and phlegm production[8,10,11]. Airway obstruction because of mucus overproduction is one of the major causes of mortality in asthma patients. Mucin 5ac (Muc5ac) protein, encoded by the Muc5ac gene is the major type of mucin, which is the main biochemical component of mucus expressed in the airway epithelium in respiratory diseases[11,13,14]. ASM, airway smooth muscle cells hypertrophy and hyperplasia; AW, airway; GCH, goblet cell hyperplasia; M, excess mucus secretion
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