Reactive oxygen species regulate Pseudomonas aeruginosa lipopolysaccharide-induced MUC5AC mucin expression via PKC-NADPH oxidase-ROS-TGF-alpha signaling pathways in human airway epithelial cells.
Mucin overproduction is a hallmark of chronic inflammatory airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Excessive production of mucin leads to airway mucus obstruction and contributes to morbidity and mortality in these diseases. The molecular mechanisms underlying mucin overproduction, however, still remain largely unknown. Here, we report that the bacterium P. aeruginosa, an important human respiratory pathogen causing cystic fibrosis, utilizes reactive oxygen species (ROS) to up-regulate MUC5AC mucin expression. Pseudomonas aeruginosa lipopolysaccharide (PA-LPS) induces production of ROS through protein kinase C (PKC)-NADPH oxidase signaling pathway in human epithelial cells. Subsequently, ROS generation by PA-LPS releases transforming growth factor-alpha (TGF-alpha), which in turn, leads to up-regulate MUC5AC expression. These findings may bring new insights into the molecular pathogenesis of P. aeruginosa infections and lead to novel therapeutic intervention for inhibiting mucin overproduction in patients with P. aeruginosa infections.
Yan
Fugui
F
Department of Respiratory Medicine, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University Institute of Respiratory Diseases, Hangzhou 310009, China.
Li
Wen
W
Jono
Hirofumi
H
Li
Qingmei
Q
Zhang
Shuangmei
S
Li
Jian-Dong
JD
Shen
Huahao
H
D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D055271:Mucin 5AC; D009077:Mucins / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism*
D008070:Lipopolysaccharides; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; D017382:Reactive Oxygen Species; D016211:Transforming Growth Factor alpha; D019255:NADPH Oxidases; D011493:Protein Kinase C