Impaired nuclear factor erythroid 2-related factor 2 expression increases apoptosis of airway epithelial cells in patients with chronic obstructive pulmonary disease due to cigarette smoking.

BACKGROUND: Cigarette smoking-induced oxidative stress is known to be a key mechanism in COPD pathogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central transcription factor that regulates the antioxidant defense system. The aim of this study was to compare Nrf2 expression in COPD subjects and control subjects, and to determine the role of Nrf2 in protecting against oxidative stress-induced apoptosis. METHODS: We enrolled 8 COPD subjects and 7 control subjects in this study. We performed bronchial brushing by bronchoscopy and obtained bronchial epithelial cells from the airways. Nrf2 expression in bronchial epithelial cells was evaluated by real-time PCR and Western blotting. We examined the effect of 10 or 15 % cigarette smoke extract (CSE) induced A549 cells apoptosis using a time-lapse cell imaging assay with caspase-3/7 activation detecting reagent and performed Terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling assay for confirming A549 cells apoptosis. We also examined the effects of Nrf2 knockdown and, 0.1, 0.5, and 1.0 mM N-acetyl cysteine on CSE-induced apoptosis. Statistical analyses were performed using t-test, paired t-test or an analysis of variance followed by the Tukey-Kramer method. RESULTS: Nrf2 mRNA expression in COPD subjects was significantly lower than that in control subjects and Nrf2 mRNA were negatively correlated with pack year. Nrf2 protein in COPD subjects was significantly lower than that in control subjects. CSE-induced A549 cells apoptosis was increased in a time-, concentration-dependent manner, and was significantly increased by Nrf2 knockdown. N-acetyl cysteine significantly ameliorated CSE-induced apoptosis. CONCLUSIONS: Nrf2 expression was lower in COPD patients than in control subjects. Nrf2 might have a protective role against apoptosis caused by CSE-induced oxidative stress. These results suggest an involvement of Nrf2 in COPD and administration of antioxidants to patients with COPD might be a basic therapeutic option.

Analysis of the contributing factors to airway hyperresponsiveness by a forced oscillation technique in patients with asthma.

BACKGROUND: Forced oscillation technique (FOT) is increasingly used to obtain much information on the state of the respiratory system. However, there are little data about FOT parameters on methacholine provocation test in adult asthma. This study was designed to determine the physiological implications of FOT parameters during methacholine provocation and analyze the major contributing factors to airway hyperresponsiveness (AHR) in asthma. METHODS: Spirometry and FOT were performed in 22 asthmatic patients and 21 normal control subjects before and after provocation with a maximal dose of methacholine. RESULTS: In asthmatic patients, the percent increase in resistance at 5 Hz (R5) and resistance at 20 Hz (R20) after the methacholine provocation was 70 [45-93] % and 16 [5-23] %. The percent change in R20 was not significantly correlated with the percent change in FVC or FEV1. Similarly, the percent change in R5 was not significantly correlated with the percent change in FEV1, but was significantly correlated with the percent change in FVC. Moreover, the percent change in R5 was significantly correlated with the closing index (r = 0.55, p = 0.01). In addition, AHR to methacholine was closely correlated with the percent change in R5 (r = -0.71, p = 0.001). CONCLUSIONS: Simultaneous measurement of FOT and bronchial challenge test provide meaningful information, and greater change in R5 may represent exaggerated response of small airways in asthmatic patients. This study will provide new insights into the physiological implications of each FOT parameter in asthmatic patients.

[A case of Wegener's granulomatosis with pachymeningitis].

A 49-year-old man was admitted to our hospital because of headache, rhinorrhea, and general fatigue. Chest CT revealed some lung nodules bilaterally, and laboratory data were positive for C-ANCA. Brain MRI revealed the findings of pachymeningitis. Wegener's granulomatosis (WG) was diagnosed by the pathological findings of his paranasal sinuses and kidneys. Most of his symptoms remarkably improved with oral corticosteroids and cyclophosphamide. A MEDLINE search about WG with pachymeningitis obtained only 15 cases previously reported in Japan. Considering those reports about WG with pachymeningitis in both Japan and overseas, in some cases pachymeningitis preceded WG, and relatively more cases than normal WG were negative for C-ANCA, furthermore the pathological findings of pachymeningitis were mainly necrotizing granuloma. Therefore pachymeningitis with WG might be mainly composed of granuloma rather than angitis and which might be a expansion of granulomatous inflammation of upper respiratory tract.

Clinical relevance of sputum cytology and chest X-ray in patients with suspected lung tumors.

OBJECTIVE: To review diagnostic procedures, therapeutic modalities, and follow-up methods in patients with suspected lung tumors. METHODS: We retrospectively examined 70 patients who underwent a complete medical checkup because they had been positive for sputum cytology and had presented no chest X-ray findings for the 10-year period between 1994 and 2004. To make a diagnosis, we conducted the first complete medical checkup that included chest X-ray, sputum cytology, chest computed tomography (CT), and bronchoscopy. In the case that no diagnosis could be made, we repeated the chest X-ray and sputum cytology every 3 to 6 months and additionally conducted chest CT and bronchoscopy according to abnormal findings. RESULTS: Among 70 patients, there were 36 and 13 who were diagnosed during the first complete medical checkup and follow-up, respectively, 13 who remained undiagnosed, and eight for whom follow-up was discontinued. Among the 49 diagnosed patients, 40, 8, and 1 patient had lung cancer, upper respiratory tract carcinoma (URTC), and esophageal carcinoma (EC), respectively. Among the 40 patients with lung cancer, 34 had a stage 0 or I tumor and 15 were radically treatable by photodynamic therapy and endobronchial irradiation. Nine among 11 patients whose lung cancer was detected during follow-up had a stage 0 or IA tumor. CONCLUSION: Not only lung cancer but also URTC and EC were successfully detected in patients who were positive for sputum cytology and presented negative chest X-ray. Radical treatment was possible in 38 (76%) of 50 diagnosed patients, thus indicating the importance of follow-up through these procedures.

[A case of intravascular lymphomatosis with no abnormal findings on chest computed tomography and with diffuse pulmonary uptake of 67Ga on scintigraphy].

A 45-year-old man was admitted to our hospital with high-grade fever uncontrolled by antipyretic drugs, and elevation of the serum LDH and sIL-2R levels, and decrease of diffusing capacity for carbon monoxide. Chest computed tomography (CT) showed no abnormal findings but 67Ga scintigraphy revealed diffuse pulmonary uptake. He was given a diagnosis of intravascular lymphomatosis (IVL) based on transbronchial lung biopsy (TBLB) and immunohistochemical analysis. The prognosis of IVL is generally bad, because antemortem diagnosis is difficult. In this case early TBLB enabled satisfactory curative effect of IVL.