PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated in many aspects of the airway pathology in asthma. TNF-alpha blocking strategies are now being tried in asthma patients. This study investigated whether TNF-alpha blocking therapy inhibits airway inflammation and airway hyperresponsiveness (AHR) in a mouse model of asthma. We also evaluated the effect of TNF-alpha blocking therapy on cytokine production and adhesion molecule expression. MATERIALS AND METHODS: Ovalbumin (OVA) sensitized BALB/c female mice were exposed to intranasal OVA administration on days 31, 33, 35, and 37. Mice were treated intraperitoneally with soluble TNF-alpha receptor (sTNFR) during the OVA challenge. RESULTS: There were statistically significant decreases in the numbers of total cell and eosinophil in bronchoalveolar lavage fluid (BALF) in the sTNFR treated group compared with the OVA group. However, sTNFR-treatment did not significantly decrease AHR. Anti-inflammatory effect of sTNFR was accompanied with reduction of T helper 2 cytokine levels including interleukin (IL)-4, IL-5 and IL-13 in BALF and vascular cell adhesion molecule 1 expression in lung tissue. CONCLUSION: These results suggest that sTNFR treatment can suppress the airway inflammation via regulation of Th2 cytokine production and adhesion molecule expression in bronchial asthma.
Animals ; Anti-Asthmatic Agents/*therapeutic use ; Asthma/*drug therapy/*immunology ; Blotting, Western ; Bronchi/drug effects ; Bronchial Hyperreactivity ; Bronchoalveolar Lavage Fluid/immunology ; Enzyme-Linked Immunosorbent Assay ; Female ; Immunohistochemistry ; Inflammation/*drug therapy ; Interleukin-13/metabolism ; Interleukin-4/metabolism ; Interleukin-5/metabolism ; Mice ; Mice, Inbred BALB C ; Ovalbumin/pharmacology ; Tumor Necrosis Factor-alpha/*therapeutic use

BACKGROUND: Tumor angiogenesis plays an important role in tumor growth, maintenance and metastatic potential. Tumor tissue produces many types of angiogenic growth factors. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have both been implicated to have roles in tumor angiogenesis. In this study, the expression of tissue VEGF and bFGF from non-small cell lung cancer (NSCLC) patients were analyzed. METHODS: We retrospectively investigated 35 patients with a histologically confirmed adenocarcinoma or squamous cell carcinoma of the lung, where the primary curative approach was surgery. An ELISA was employed to determine the expression of VEGF and bFGF in extracts prepared from 35 frozen tissue samples taken from the cancer patients. RESULTS: VEGF and bFGF concentrations were significantly increased in lung cancer tissue as compared with control (non-cancerous) tissue. The VEGF concentration was significantly increased in T2 and T3 cancers as compared with T1 cancer. Expression of VEGF was increased in node-positive lung cancer tissue as compared with node-negative lung cancer tissue (p=0.06). VEGF and bFGF expression were not directly related to the stage of lung cancer and patient survival. CONCLUSION: Expression of VEGF and bFGF were increased in lung cancer tissue, and the expression of VEGF concentration in lung cancer tissue was more likely related with tumor size and the presence of a lymph node metastasis than the expression of bFGF. However, in this study, expression of both VEGF and bFGF in tissue were not associated with patient prognosis.
Adenocarcinoma ; Carcinoma, Non-Small-Cell Lung ; Carcinoma, Squamous Cell ; Enzyme-Linked Immunosorbent Assay ; Fibroblast Growth Factor 2 ; Humans ; Intercellular Signaling Peptides and Proteins ; Lung ; Lung Neoplasms ; Lymph Nodes ; Neoplasm Metastasis ; Prognosis ; Retrospective Studies ; Vascular Endothelial Growth Factor A

Although animal models with ovalbumin have been used to study chronic asthma, there are difficulties in inducing recurrence as well as in maintaining chronic inflammation in this system. Using a murine model of house dust mite (HDM)-induced bronchial asthma, we examined the airway remodeling process in response to the chronic exposure to HDM. During the seventh and twelfth weeks of study, HDM were inhaled through the nose for three consecutive days and airway responsiveness was measured. Twenty-four hours later, bronchoalveolar lavage and histological examination were performed. The degree of overproduction of mucus, subepithelial fibrosis, and the thickness of the peribronchial smooth muscle in the experimental group was clearly increased compared to the control group. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. In the bronchoalveolar lavage fluid, the number of total cells and eosinophils was increased; during the twelfth week, the number of neutrophils increased in the experimental group. With regard to changes in cytokines, the concentrations of IL-4, IL- 13, and transforming growth factor-beta (TGF-beta) were increased in the experimental group. The data suggest that eosinophils, IL-4, IL-13, and TGF-beta might play an important role in the airway remodeling process and that neutrophils may be involved with increased exposure time.
Animals ; Asthma/*etiology/pathology ; Eosinophils/physiology ; Female ; Immunoglobulin E/blood ; Immunoglobulin G/blood ; Inflammation/*etiology ; Interleukin-13/physiology ; Interleukin-4/physiology ; Lung/*pathology ; Mice ; Mice, Inbred BALB C ; Pyroglyphidae/*immunology ; Transforming Growth Factor beta/physiology

During the course of establishing an animal model of chronic asthma, we tried to elucidate the time sequence of airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, and associated cytokines. Seven-week-old female BALB/c mice were studied as a chronic asthma model using ovalbumin (OVA). After sensitization, mice were exposed twice weekly to aerosolized OVA, and were divided into three groups depending on the duration of 4 weeks, 8 weeks, and 12 weeks. At each time point, airway responsiveness, inflammatory cells, cytokines in bronchoalveolar lavage fluids (BALF), serum OVA-specific IgE, IgG1, IgG2a, and histological examination were carried out. AHR to methacholine, increased levels of OVA-specific IgG1 and IgG2a, and goblet cell hyperplasia were continuously sustained at each time point of weeks. In contrast, we observed a time-dependent decrease in serum OVA-specific IgE, BALF eosinophils, BALF cytokines such as IL-13, transforming growth factor-beta1, and a time-dependent increase in BALF promatrix metalloproteinase-9 and peribronchial fibrosis. In this OVA-induced chronic asthma model, we observed airway remodelings as well as various cytokines and inflammatory cells being involved in different time-dependent manners. However, increased airway fibrosis did not directly correlate with a further increase in airway hyperresponsiveness.
Time Factors ; Pneumonia/chemically induced/*immunology ; Ovalbumin ; Mice, Inbred BALB C ; Mice ; Lung/drug effects/*immunology ; Female ; *Disease Models, Animal ; Cytokines/*immunology ; Chronic Disease ; Asthma/chemically induced/*immunology ; Animals

We experienced a rare case of trachea diverticula combined with the sequela of tuberculosis and a fungus ball. The patient had complained of coughing and hemoptysis for a long time after experiencing tuberculosis. He was admitted due to hemoptysis and the aggravation of coughing. The CT scan showed a variable sized trachea diverticula combined with tuberculosis sequela and a fungus ball in the right lung fields. The diagnosis was made by bronchoscopy and a CT scan. After bronchial artery embolization and conservative treatment, the patient's symptoms improved and the patient was discharged.
Bronchial Arteries ; Bronchoscopy ; Cough ; Diagnosis ; Diverticulum* ; Fungi* ; Hemoptysis* ; Humans ; Lung ; Tomography, X-Ray Computed ; Trachea ; Tuberculosis*

BACKGROUND: The aberrant promoter hypermethylation of p16(INK4a), as a tumor suppressor gene, is contributory factor to non-small cell lung cancer(NSCLC). However, its potential diagnostic impact of lung cancer is unclear. This study measured the level of p16(INK4a) promoter hypermethylation in the sputum and blood, and compared this with the level measured in the tissue obtained from NSCLC and pulmonary inflammation. METHODS: Of the patients who visited the Our Lady of Mercy Hospital in Incheon, Korea for an evaluation of a lung mass and underwent blood, sputum, and tissue tests, 23patients (18 NSCLC, 5 pulmonary inflammation) were enrolled in this study. DNA was extracted from each sample and the level of p16(INK4a) methylation was determined using methylation-specific polymerase chain reaction. RESULTS: p16(INK4a) methylation of the blood was observed in 88.9% (16 of 18) and 20.0% (1 of 5) of NSCLC and from pulmonary inflammation samples, respectively (P=0.008). Methylation of the sputum was observed in 83.3% (10 of 12) 80.0% (4 of 5) of NSCLC and pulmonary inflammation samples, respectively (P=1.00). Among the 8 NSCLC tissue samples, methylation changes were detected in 75.0% of samples (6 cases). Four out of seven tissue samples (57.1%) showed concordance, being methylated in both the blood and sputum. CONCLUSIONS: There was a higher level of p16(INK4a) methylation of the blood from NSCLC patients than from pulmonary inflammation. The tissue showed a high concordance with the blood in the NSCLC samples. These findings suggest that p16(INK4a) promoter hypermethylation of the blood can used to discriminate between NSCLC and pulmonary inflammation.
Carcinoma, Non-Small-Cell Lung* ; Cyclin-Dependent Kinase Inhibitor p16* ; DNA ; Genes, Tumor Suppressor ; Humans ; Incheon ; Korea ; Lung ; Lung Neoplasms ; Methylation ; Pneumonia* ; Polymerase Chain Reaction ; Sputum*

BACKGROUND: The objective of this study was to understand sleep-related problems, and to determine whether the sleep questionnaires is a clinically useful method in patients who need polysomnography. METHODS: Subjects were patients who performed polysomnography and who asked to answer a sleep questionnaires at the Sleep Disorders Clinic of St. Paul's Hospital, Catholic University of Korea. Baseline characteristics, past medical illness, behaviors during sleep-wake cycle, snoring, sleep-disordered breathing and symptoms of daytime sleepiness were analyzed to compare with data of polysomnography. RESULTS: The study population included 1081 patients(849 men, 232 female), and their mean age was 44.2+/-12.8 years. Among these patients, 38.9% had an apnea-hypopnea index(AHI) < 5, 27.9% had 5 < or = AHI < 20, 13.2% had 20 < or = AHI < 40, and 20.0% had 40 < or = AHI. The main problems for visiting our clinic were snoring(91.7%), sleep apnea(74.5%), excessive daytime sleepiness(8.0%), insomnia(4.3%), bruxism(1.1%) and attention deficit(0.5%). The mean value of frequency of interruptions of sleep was 1.6 and the most common reason was urination(46.3%). Epworth Sleepiness Scale(ESS) had a weak correlation with AHI(r=0.209, p<0.01). When we performed analysis of sleep questionnaires, there were significant differences in the mean values of AHI according to the severity of symptoms including snoring, daytime sleepiness, taking a nap and arousal state after wake(p<0.05). CONCLUSION: On the basis of statistical analysis of sleep questionnaires, the severity of subjective symptoms such as ESS, snoring, daytime sleepiness and arousal state after wake correlated with the AHI significantly. Therefore the sleep questionnaires can be useful instruments for prediction of the severity of sleep disorder, especially sleep-disordered breathing.
Arousal ; Humans ; Korea ; Male ; Polysomnography* ; Surveys and Questionnaires* ; Sleep Apnea Syndromes ; Sleep Apnea, Obstructive ; Sleep Wake Disorders ; Snoring

BACKGROUND: The objective of this study was to understand sleep-related problems, and to determine whether the sleep questionnaires is a clinically useful method in patients who need polysomnography. METHODS: Subjects were patients who performed polysomnography and who asked to answer a sleep questionnaires at the Sleep Disorders Clinic of St. Paul's Hospital, Catholic University of Korea. Baseline characteristics, past medical illness, behaviors during sleep-wake cycle, snoring, sleep-disordered breathing and symptoms of daytime sleepiness were analyzed to compare with data of polysomnography. RESULTS: The study population included 1081 patients(849 men, 232 female), and their mean age was 44.2+/-12.8 years. Among these patients, 38.9% had an apnea-hypopnea index(AHI) < 5, 27.9% had 5 < or = AHI < 20, 13.2% had 20 < or = AHI < 40, and 20.0% had 40 < or = AHI. The main problems for visiting our clinic were snoring(91.7%), sleep apnea(74.5%), excessive daytime sleepiness(8.0%), insomnia(4.3%), bruxism(1.1%) and attention deficit(0.5%). The mean value of frequency of interruptions of sleep was 1.6 and the most common reason was urination(46.3%). Epworth Sleepiness Scale(ESS) had a weak correlation with AHI(r=0.209, p<0.01). When we performed analysis of sleep questionnaires, there were significant differences in the mean values of AHI according to the severity of symptoms including snoring, daytime sleepiness, taking a nap and arousal state after wake(p<0.05). CONCLUSION: On the basis of statistical analysis of sleep questionnaires, the severity of subjective symptoms such as ESS, snoring, daytime sleepiness and arousal state after wake correlated with the AHI significantly. Therefore the sleep questionnaires can be useful instruments for prediction of the severity of sleep disorder, especially sleep-disordered breathing.
Arousal ; Humans ; Korea ; Male ; Polysomnography* ; Surveys and Questionnaires* ; Sleep Apnea Syndromes ; Sleep Apnea, Obstructive ; Sleep Wake Disorders ; Snoring

OBJECT: Cigarette smoking is a major cause of mucus hypersecretion, which is a pathophysiological feature of many inflammatory airway diseases. Mucins, which are an important part of the airway mucus, are synthesized from the Muc gene in airway epithelial cells. However, the signaling pathways for cigarette smoke-induced mucin synthesis are unknown. The aim of this study was to determine the signal pathway for smoking induced Muc5ac gene expression. METHODS: A549 cells were cultured and transiently transfected with the Muc5ac promoter fragment. These cells were stimulated with 5% cigarette smoke extract (CSE) alone or with CSE after a pretreatment with various signal transduction pathway inhibitors (AG1478, PD98059 and SB203580). The Muc5ac promoter activity was examined using the luciferase reporter system, and the level of phosphorylated EGFR, ERK1/2, p38 MAPK and JNK were all examined using Western blot analysis. Muc5ac mRNA expression was also examined using reverse transcriptase polymerase chain reactions (RT-PCR). RESULTS: 1. The peak level of luciferase activity of the Muc5ac promoter was observed at 5% concentration and after 3 hours of incubation with the CSE. The level of EGFR phosphorylation and the luciferase activity of the transfected cells caused by the CSE were significantly suppressed by AG1478 or PD98059 (P<0.01). 2. CSE phosphorylated ERK1/2 or p38 MAPK but not JNK. The Muc5ac mRNA expression level was increased by the CSE but that was suppressed by PD98059 or AG1478. 3. The CSE-induced phosphorylation of ERK1/2 was blocked by PD98059 and that of p38 MAPK was blocked by either PD98059 or SB203580. Either PD98059 or SB203580 suppressed the luciferase activity of the transfected cells (P<0.0001). CONCLUSION: The Muc5ac mRNA expression level was increased by the CSE. The increased CSE-induced transcriptional activity was mediated via EGF receptor activation, which led to ERK1/2 and p38 MAPK phosphorylation.
Blotting, Western ; Epithelial Cells ; Gene Expression* ; Luciferases ; Mucins ; Mucus ; p38 Mitogen-Activated Protein Kinases* ; Phosphorylation ; Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor ; RNA, Messenger ; RNA-Directed DNA Polymerase ; Signal Transduction ; Smoke* ; Smoking ; Tobacco Products*

Patients with acromegaly have high incidence of benign or malignant neoplasia than general population. Around fifteen percent of the deaths reported in acromegaly are attributable to malignancy of cancer. On the whole, mortality in acromegaly has been shown to be correlated with the degree of growth hormone (GH) control. Especially, the levels of insulin like growth factor-1 (IGF-1) may be higher in neoplasm, but there is no clear evidence to prove that tumor development is triggered by IGF-1 in acromegaly. Henceforth, we report a case of acromegaly associated with lung and gastric cancer in a 58-year-old man, suggesting the possible carcinogenic role of IGF-1.
Acromegaly* ; Growth Hormone ; Humans ; Incidence ; Insulin ; Insulin-Like Growth Factor I ; Lung Neoplasms ; Lung* ; Middle Aged ; Mortality ; Stomach Neoplasms*