title: Decreased airway expression of vascular endothelial growth factor in cigarette smoke-induced emphysema in mice and COPD patients.
abstract: Vascular endothelial growth factor (VEGF) signaling is crucial for lung structure maintenance. Although VEGF deficiency plays a role in the pathogenesis of emphysema in animals, little is known about VEGF expression levels and functions, as well as VEGF receptors, in airway epithelial cells, which are in direct contact with the environment. In this study, C57BL/6J mice were exposed to cigarette smoke (CS) for short (approximately 10 days) and long (4-24 wk) time periods, and bronchiolar expressions of VEGF and its receptors VEGFR-1 and VEGFR-2 were examined. The relationships between the expressions of VEGF, VEGFR-1, and VEGFR-2 and smoking histories and/or chronic obstructive pulmonary disease (COPD) were examined in humans. The mRNA levels were quantified in bronchiolar epithelium harvested by laser capture microdissection in both mouse and human lung tissues or in human bronchial epithelium harvested by bronchoscopic brushing. The VEGF protein level was assessed by immunohistochemistry or enzyme-linked immunosorbent assay. Repeated CS exposure downregulated bronchiolar expressions of VEGF and both VEGF receptors at various time points prior to the development of emphysema. In humans, bronchiolar VEGF was significantly decreased in smokers with COPD compared to lifelong nonsmokers, as well as to smokers without COPD; however, there was no difference in bronchiolar VEGF levels between lifelong nonsmokers and smokers without COPD. On the other hand, bronchiolar VEGFR-2 was downregulated in smokers with and without COPD compared to lifelong nonsmokers. These findings suggest the association of downregulation of bronchiolar VEGF and its receptors with cigarette smoking and COPD.
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.forename: Katsura
authors.initials: K
authors.lastname: Nagai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fuke
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nasuhara
authors.forename: Kichizo
authors.initials: K
authors.lastname: Kaga
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kondo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hamamura
authors.forename: Junko
authors.initials: J
authors.lastname: Hata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
mesh_terms: D000368:Aged; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012906:Smoke / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D012906:Smoke; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2