Guanine nitration in idiopathic pulmonary fibrosis and its implication for carcinogenesis.
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.
Terasaki
Yasuhiro
Y
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Osaka, Japan.
Akuta
Teruo
T
Terasaki
Mika
M
Sawa
Tomohiro
T
Mori
Takeshi
T
Okamoto
Tatsuya
T
Ozaki
Masakazu
M
Takeya
Motohiro
M
Akaike
Takaaki
T
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
C095838:8-nitroguanine; D006147:Guanine