title: Guanine nitration in idiopathic pulmonary fibrosis and its implication for carcinogenesis.
abstract: BACKGROUND
  Nitric oxide (NO)-induced nitrative stress of nucleic acids, as evidenced by guanine nitration, appears to be involved in inflammation-induced carcinogenesis. A high incidence of lung cancer in idiopathic pulmonary fibrosis (IPF) is the major reason for poor prognosis in patients with IPF.
  
  
  OBJECTIVE
  We immunohistochemically analyzed the formation and localization of 8-nitroguanine in lung tissues from control subjects, patients with IPF, and patients with lung cancer.
  
  
  RESULTS
  Immunohistochemical analysis of control smoker and nonsmoker lungs showed weak immunoreactivity for 8-nitroguanine, mainly in cytoplasm of bronchial epithelial cells. In addition to the bronchial epithelial cells, metaplastic regenerated epithelial cells overlying dense fibrotic lesions in IPF showed strong 8-nitroguanine staining in the cytoplasm. The staining in these metaplastic cells colocalized with staining of inducible and endothelial NO synthases and 8-oxodeoxyguanosine, as evidenced by double-immunostaining analysis. Confocal and immunoelectron microscopy revealed localization of 8-nitroguanine in metaplastic epithelial cytoplasm, mostly in mitochondria. Appreciable 8-nitroguanine immunostaining was also observed in both nuclei and cytoplasm of malignant epithelial cells in squamous cell carcinoma. No significant difference was found in the epithelial 8-nitroguanine formation between control smokers and nonsmokers, but much higher guanine nitration was observed in patients with IPF than in control subjects and patients with lung cancer, via a quantitative immunofluorescence image analysis.
  
  
  CONCLUSIONS
  The present study indicates that not only oxidative stress but also nitrative stress induced by NO may participate in the pathogenesis of epithelial cell damage and aberrant regeneration occurring in IPF. Thus, guanine nitration may be a major risk factor for lung cancer development in IPF.
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Osaka, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Terasaki
authors.forename: Teruo
authors.initials: T
authors.lastname: Akuta
authors.forename: Mika
authors.initials: M
authors.lastname: Terasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mori
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okamoto
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ozaki
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Takaaki
authors.initials: T
authors.lastname: Akaike
mesh_terms: D000328:Adult; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D042541:Intracellular Space / Q000378:metabolism / Q000648:ultrastructure; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008875:Middle Aged; D011379:Prognosis; D011658:Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D012189:Retrospective Studies
chemical_list: C095838:8-nitroguanine; D006147:Guanine