Guanine Nitration in Idiopathic Pulmonary Fibrosis and Its Implication for Carcinogenesis

• Published in: American journal of respiratory and critical care medicine Vol. 174; no. 6; pp. 665 - 673
• Main Authors: Terasaki, Yasuhiro, Akuta, Teruo, Terasaki, Mika, Sawa, Tomohiro, Mori, Takeshi, Okamoto, Tatsuya, Ozaki, Masakazu, Takeya, Motohiro, Akaike, Takaaki
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.09.2006; American Lung Association; American Thoracic Society
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Biopsy; Carcinoma, Squamous Cell - etiology; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Disease Progression; Female; Guanine - analogs & derivatives; Guanine - metabolism; Humans; Immunohistochemistry; Intensive care medicine; Intracellular Space - metabolism; Intracellular Space - ultrastructure; Lung - metabolism; Lung - pathology; Lung Neoplasms - etiology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical sciences; Microscopy, Confocal; Microscopy, Immunoelectron; Middle Aged; Pneumology; Prognosis; Pulmonary Fibrosis - complications; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Respiratory system : syndromes and miscellaneous diseases; Retrospective Studies; Lung disease; 8-nitroguanine; Intensive care; Respiratory disease; Lung cancer; Idiopathic; Malignant tumor; Carcinogenesis; Stress; Pulmonary fibrosis; Interstitial pneumonitis; Bronchus disease; nitrative stress; tumorigenesis; Resuscitation; idiopathic pulmonary fibrosis/usual interstitial pneumonia
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200510-1580OC

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. We immunohistochemically analyzed the formation and localization of 8-nitroguanine in lung tissues from control subjects, patients with IPF, and patients with lung cancer. 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. 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.