title: CFTR-regulated MAPK/NF-κB signaling in pulmonary inflammation in thermal inhalation injury.
abstract: The mechanism underlying pulmonary inflammation in thermal inhalation injury remains elusive. Cystic fibrosis, also hallmarked with pulmonary inflammation, is caused by mutations in CFTR, the expression of which is temperature-sensitive. We investigated whether CFTR is involved in heat-induced pulmonary inflammation. We applied heat-treatment in 16HBE14o- cells with CFTR knockdown or overexpression and heat-inhalation in rats in vivo. Heat-treatment caused significant reduction in CFTR and, reciprocally, increase in COX-2 at early stages both in vitro and in vivo. Activation of ERK/JNK, NF-κB and COX-2/PGE2 were detected in heat-treated cells, which were mimicked by knockdown, and reversed by overexpression of CFTR or VX-809, a reported CFTR mutation corrector. JNK/ERK inhibition reversed heat-/CFTR-knockdown-induced NF-κB activation, whereas NF-κB inhibitor showed no effect on JNK/ERK. IL-8 was augmented by heat-treatment or CFTR-knockdown, which was abolished by inhibition of NF-κB, JNK/ERK or COX-2. Moreover, in vitro or in vivo treatment with curcumin, a natural phenolic compound, significantly enhanced CFTR expression and reversed the heat-induced increases in COX-2/PGE2/IL-8, neutrophil infiltration and tissue damage in the airway. These results have revealed a CFTR-regulated MAPK/NF-κB pathway leading to COX-2/PGE2/IL-8 activation in thermal inhalation injury, and demonstrated therapeutic potential of curcumin for alleviating heat-induced pulmonary inflammation.
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Zhi Wei
authors.initials: ZW
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Ye Chun
authors.initials: YC
authors.lastname: Ruan
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: YaJie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Tsang
authors.affiliation: Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Hsiao Chang
authors.initials: HC
authors.lastname: Chan
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Key Laboratory for Proteomics Disease, Institute of Burn Research, Southwest Hospital, the Third Military Medical University, Chongqing, China.
authors.forename: Yi Zhi
authors.initials: YZ
authors.lastname: Peng
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006358:Hot Temperature; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D001239:Inhalation; D016209:Interleukin-8 / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008171:Lung Diseases / Q000209:etiology / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C569105:lumacaftor; D003474:Curcumin; D015232:Dinoprostone