Abstract
Exposure to lipopolysaccharides (LPS) causes extensive neutrophilic inflammation in the airways followed by mucous cell hyperplasia (MCH) that is sustained by the anti-apoptotic protein, Bcl-2. To identify inflammatory factor(s) that are responsible for Bcl-2 expression, we established an organ culture system consisting of airway epithelial tissue from the rat nasal midseptum. The highest Muc5AC and Bcl-2 expression was observed when organ cultures were treated with brochoalveolar lavage (BAL) fluid harvested from rats 10 h post LPS instillation. Further, because BAL harvested from rats depleted of polymorphonuclear cells compared to controls showed increased Bcl-2 expression, analyses of cytokine levels in lavages identified IL-13 as an inducer of Bcl-2 expression. Ectopic IL-13 treatment of differentiated airway epithelial cells increased Bcl-2 and MUC5AC expression in the basal and apical regions of the cells, respectively. When Bcl-2 was blocked using shRNA or a small molecule inhibitor, ABT-263, mucous cell numbers were reduced due to increased apoptosis that disrupted the interaction of Bcl-2 with the pro-apoptotic protein, Bik. Furthermore, intranasal instillation of ABT-263 reduced the LPS-induced MCH in bik+/+ but not bik−/− mice, suggesting that Bik mediated apoptosis in hyperplastic mucous cells. Therefore, blocking Bcl-2 function could be useful in reducing IL-13 induced mucous hypersecretion.
Highlights
Because of its importance in various biological processes and diseases, understanding the regulation of Bcl-2 expression is very critical
Our previous studies showed that exposure of rodent lungs to LPS causes extensive neutrophilic inflammation and mucous cell hyperplasia that is sustained by Bcl-2 expression in epithelial mucous cells[26,27,33,35,36,41]
LPS-induced inflammation is characterized by an initial influx of large number of polymorphonuclear cells (PMNs) over the first 3–8 h followed by macrophages and lymphocytes over 6–12 h post LPS instillation[36]
Summary
Because of its importance in various biological processes and diseases, understanding the regulation of Bcl-2 expression is very critical. Bcl-2 levels are regulated by various cytokines, including IL-1β and IGF-1 in airway epithelial cells[5,6], IL-6 in lymphoblast cells[7], IL-7 and IL-21 in T lymphoid cells[8,9], IL-10 in tumor-associated macrophages[10], andIL-22 in renal cortex tissue[11] Many of these cytokines converge into the NF-κB pathway[12,13] and other signaling molecules like janus kinase/signal transducer and activator of transcription (JAK/STAT)[14,15] and phosphatidylinositol 3-kinase (PI3K)/PKB (protein kinase B)[16,17] to increase Bcl-2 expression. Following inflammatory responses to LPS or allergen exposure, Bcl-2 expression is upregulated in airway epithelial cells of animal models of mucous hypersecretion and in patients with cystic fibrosis, asthma, and chronic bronchitis[5,26,27]. The goal of the present study was to understand the pathways responsible for the coordinated induction of Bcl-2 and MUC5AC in AECs and help to identify novel intervention strategies to control mucous cell hyperplasia. We further found that ABT-263 at very low doses alleviated LPS-induced mucous cell hyperplasia (MCH)
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