Airway mucus overproduction and epithelial mucous cell hyperplasia/metaplasia are clinical hallmarks associated with various airway diseases, such as COPD, cystic fibrosis and asthma. Despite the pathological significance of the excess mucus in these diseased airways, the cause and the mechanism of the aberrant mucus production is largely unknown. We have shown a """"""""metaplastic"""""""" change of surface airway epithelial cells from the sole expression of the """"""""surface"""""""" type of gel-forming mucin -MUC5AC to the co-expression with the submucosal gland-specific MUC5B and MUC19, a novel gel-forming we newly discovered, in airway diseases. Most recently, Muc19 locus has been shown to be genetically associated with salivary gland mucous cell development. A mouse having a single mutation (sld) in Muc19 locus shows mucous cell deficiency in their salivary gland. We have recently found that the mouse containing sld mutation also has much less submucosal gland mucous cells and less Muc19 expression. Thus, Muc19 locus appears to control glandular mucous cell development. Importantly, different from MUC5AC, which is elevated by IL-13 after long term treatment, this newly found gel-forming mucin gene-MUC19, can be stimulated by Th2 cytokines (IL-4 and IL-13) in a short-term (24h). Thus, we hypothesize that the induction of MUC19/Muc19 by Th2 cytokine may represent a key early event, seemingly to promote glandular phenotype, in the development of mucous cell metaplasia in asthmatic airway. To test the hypothesis, four aims are proposed: 1) To test the hypothesis that MUC19 production is significantly elevated in asthmatic airway. 2) To test the hypothesis that Muc19 expression is essential for mucous cell development. 2) To test the hypothesis that Th2 cytokine transcriptionally activates MUC19 gene expression in vitro. 3) To test the hypothesis that Th2 cytokine induced Muc19 expression and mucous cell metaplasia are regulated by the interaction of Stat1 and Stat6 in vivo. The success of this project will significantly advance our understanding of Th2 cytokine effect on development of epithelial mucus overproduction and mucous cell metaplasia, which will accelerate the development of specific epithelium-targeting therapeutic agents to treat asthma. ? ? ?
| Zhou, Xu; Zhu, Lingxiang; Lizarraga, Rosa et al. (2017) Human Airway Epithelial Cells Direct Significant Rhinovirus Replication in Monocytic Cells by Enhancing ICAM1 Expression. Am J Respir Cell Mol Biol 57:216-225 |
| Oslund, Karen L; Zhou, Xu; Lee, Boram et al. (2014) Synergistic up-regulation of CXCL10 by virus and IFN ? in human airway epithelial cells. PLoS One 9:e100978 |
| Zhu, Lingxiang; Lee, Boram; Zhao, Fangkun et al. (2014) Modulation of airway epithelial antiviral immunity by fungal exposure. Am J Respir Cell Mol Biol 50:1136-43 |
| Zhu, Lingxiang; Barrett, Erika C; Barret, Erika C et al. (2013) Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2. PLoS One 8:e55695 |
| Tao, Shasha; Zhu, Lingxiang; Lee, Pakkei et al. (2012) Negative control of TLR3 signaling by TICAM1 down-regulation. Am J Respir Cell Mol Biol 46:660-7 |
| Floyd, Anne M; Zhou, Xu; Evans, Christopher et al. (2012) Mucin deficiency causes functional and structural changes of the ocular surface. PLoS One 7:e50704 |
| Fujisawa, Tomoyuki; Chang, Mary Mann-Jong; Velichko, Sharlene et al. (2011) NF-?B mediates IL-1?- and IL-17A-induced MUC5B expression in airway epithelial cells. Am J Respir Cell Mol Biol 45:246-52 |
| Zhu, Lingxiang; Lee, Pakkei; Yu, Dongfang et al. (2011) Cloning and characterization of human MUC19 gene. Am J Respir Cell Mol Biol 45:348-58 |
| Yu, Dongfang; Walters, Dianne M; Zhu, Lingxiang et al. (2011) Vanadium pentoxide (V(2)O(5)) induced mucin production by airway epithelium. Am J Physiol Lung Cell Mol Physiol 301:L31-9 |
| Zhu, Lingxiang; Lee, Pak-Kei; Lee, Wai-Ming et al. (2009) Rhinovirus-induced major airway mucin production involves a novel TLR3-EGFR-dependent pathway. Am J Respir Cell Mol Biol 40:610-9 |
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