Abstract
Mucus hypersecretion by airway epithelium is a hallmark of inflammation in allergic asthma and results in airway narrowing and obstruction. Others have shown that administration a TH2 cytokine, IL-13 is sufficient to cause mucus hypersecretion in vivo and in vitro. Asthma therapy often utilizes β2-adrenoceptor (β2AR) agonists, which are effective acutely as bronchodilators, however chronic use may lead to a worsening of asthma symptoms. In this study, we asked whether β2AR signaling in normal human airway epithelial (NHBE) cells affected mucin production in response to IL-13. This cytokine markedly increased mucin production, but only in the presence of epinephrine. Mucin production was blocked by ICI-118,551, a preferential β2AR antagonist, but not by CGP-20712A, a preferential β1AR antagonist. Constitutive β2AR activity was not sufficient for IL-13 induced mucin production and β-agonist-induced signaling is required. A clinically important long-acting β-agonist, formoterol, was as effective as epinephrine in potentiating IL-13 induced MUC5AC transcription. IL-13 induced mucin production in the presence of epinephrine was significantly reduced by treatment with selective inhibitors of ERK1/2 (FR180204), p38 (SB203580) and JNK (SP600125). Replacement of epinephrine with forskolin + IBMX resulted in a marked increase in mucin production in NHBE cells in response to IL-13, and treatment with the inhibitory cAMP analogue Rp-cAMPS decreased mucin levels induced by epinephrine + IL-13. Our findings suggest that β2AR signaling is required for mucin production in response to IL-13, and that mitogen activated protein kinases and cAMP are necessary for this effect. These data lend support to the notion that β2AR-agonists may contribute to asthma exacerbations by increasing mucin production via activation of β2ARs on epithelial cells.
Highlights
Asthma is a chronic inflammatory disease characterized by airway hyperreactivity, subepithelial fibrosis, airway smooth muscle hyperplasia and mucous metaplasia [1]
Airway epithelium is essential and sufficient for mucous metaplasia induced by IL-13, and this is dependent on the expression of STAT6 in the epithelium [7]
IL-13 plays an important role in the mucus over-production characteristic of bronchial asthma, and MUC5AC is the major mucin gene that is overexpressed by airway epithelium in asthmatic patients [22, 23]
Summary
Asthma is a chronic inflammatory disease characterized by airway hyperreactivity, subepithelial fibrosis, airway smooth muscle hyperplasia and mucous metaplasia [1]. Mucous metaplasia is an increase in the number of mucus-secreting goblet cells in the epithelium [2] that results in increased mucus synthesis and secretion. Excessive accumulation of airway mucus leads to the formation of mucous plugs that reduce the effective airway diameter and increase airway resistance. Patients who die of severe asthma attacks often exhibit goblet cell hyperplasia, mucus accumulation and large mucus plugs of unusual solidity due to high mucin content in their peripheral airways compared to asthmatic patients who did not die of acute attacks [3]. The allergic airway contains diverse hematopoietic and parenchymal cells, and factors secreted by them, airway epithelial overexpression of IL-13 or airway instillation of IL-13 is sufficient to induce mucous metaplasia in mice [5, 6]. Sputum of asthmatic patients show elevated levels of IL13 and its presence is negatively associated with therapeutic responsiveness [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
