title: Pseudomonas aeruginosa pyocyanin causes airway goblet cell hyperplasia and metaplasia and mucus hypersecretion by inactivating the transcriptional factor FoxA2.
abstract: The redox-active exotoxin pyocyanin (PCN) can be recovered in 100 µM concentrations in the sputa of bronchiectasis patients chronically infected with Pseudomonas aeruginosa (PA). However, the importance of PCN within bronchiectatic airways colonized by PA remains unrecognized. Recently, we have shown that PCN is required for chronic PA lung infection in mice, and that chronic instillation of PCN induces goblet cell hyperplasia (GCH), pulmonary fibrosis, emphysema and influx of immune cells in mouse airways. Many of these pathological features are strikingly similar to the mouse airways devoid of functional FoxA2, a transcriptional repressor of GCH and mucus biosynthesis. In this study, we postulate that PCN causes and exacerbates GCH and mucus hypersecretion in bronchiectatic airways chronically infected by PA by inactivating FoxA2. We demonstrate that PCN represses the expression of FoxA2 in mouse airways and in bronchial epithelial cells cultured at an air-liquid interface or conventionally, resulting in GCH, increased MUC5B mucin gene expression and mucus hypersecretion. Immunohistochemical and inhibitor studies indicate that PCN upregulates the expression of Stat6 and EGFR, both of which in turn repress the expression of FoxA2. These studies demonstrate that PCN induces GCH and mucus hypersecretion by inactivating FoxA2.
authors: Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors: Yonghua
authors: Y
authors: Hao
authors: Zhizhou
authors: Z
authors: Kuang
authors: Brent E
authors: BE
authors: Walling
authors: Shikha
authors: S
authors: Bhatia
authors: Mayandi
authors: M
authors: Sivaguru
authors: Yin
authors: Y
authors: Chen
authors: H Rex
authors: HR
authors: Gaskins
authors: Gee W
authors: GW
authors: Lau
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D066246:ErbB Receptors / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D006965:Hyperplasia; D008168:Lung / Q000382:microbiology / Q000473:pathology*; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055257:Mucin-5B / Q000235:genetics / Q000378:metabolism; D009093:Mucus / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000502:physiology*; D011710:Pyocyanine / Q000378:metabolism* / Q000494:pharmacology; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C496503:Foxa2 protein, mouse; C524578:MUC5B protein, human; D055257:Mucin-5B; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; D011710:Pyocyanine; D066246:ErbB Receptors