• Tuberculosis and Respiratory Diseases
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• v.45 no.4
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• pp.723-735
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• 1998

Background : Vitamin C has been reported to have a role in the decrease of airway hyperresponsiveness in animal models. This data is based on some metabolic actions of vitamin C, such as promotion of histamine degradation, producing more $PGE_2$ than $PGF_{2\alpha}$ in cyclooxygenase pathway, decrease of smooth muscle contraction, and acting as reducing agent of oxidant. It has been also known that heavy smokers have lower blood levels of vitamin C than nonsmokers and this deficiency in heavy smokers have been explained by several mechanisms, such as increased oxidation by oxidants and free radicals, increased biosynthesis of catecholamine and serotonin released by nicotine, and inadequate dietary intake. In this study, We attempted to assess effect of vitamin C on bronchial hyperresponsiveness in heavy smokers who have bronchial hyperresponsiveness and role of vitamin C on bronchial hyperresponsiveness. Method: To assess acute effect of vitamin C on airway hyperresponsiveness, blood sample for vitamin C level and spirometry, methacholine challenge test were done in 17 smokers and 8 nonsmokers, and one hour after oral administration of vitamin C 3 g, blood sample for vitamin C level and spirometry, methacholine challenge test were repeated. To assess chronic effect of vitamin C on airway hyperresponsiveness, after daily administration of vitamin C 1 g for one week in 17 smokers, blood sample for vitamin C level and spirometry, methacholine challenge test were done. To assess role of vitamin C, after oral administration of vitamin C 3 g plus indomethacin 100 mg in 12 of 15 smokers who were reactive to methacholine challenge test, spirometry and methacholine challenge test were done and after oral intake of indomethacin 100 mg in 12 smokers who were reactive to methacholine challenge test, spirometry and methacholine challenge test were repeated. Result: There were no significant differences in whole blood vitamin C levels between smokers($1.17{\pm}0.22$ mg/dL) and nonsmcikers($1.14{\pm}0.19$ mg/dL) (p>0.05). Fifteen of the 17 smokers(88.2%) were reactive to methacholine challenge test and 10 of the 15 smokers who were reactive to methacholine challenge test were less than 8 mg/dL in $PC_{20}FEV-2$, and 7 of the 8 nonsmokers(87.5%) were nonreactive to methacholine challenge test There were significant decrease in bronchial responsiveness after oral administration of vitamin C 3 g in 13 of the 15 smokers who were reactive to methacholine challenge test This significant decrease persisted with maintenance daily administration of 1 g for one week. $PC_{20}FEV-2$ were not correlated to vitamin C levels in smokers. After oral administration of indomethacin 100 mg, significant reduction of bronchial responsiveness that occured after oral administration of vitamin C 3 g in smokers were attenuated. Conclusion: Although there were no significant differences in whole blood vitamin C levels between smokers and nonsmokers. heavy smokers have significant increase in bronchial responsiveness than nonsmokers. This bronchial hyperresponsiveness of heavy smokers can be attenuated by vitamin C supplement. Disappearance of vitamin C effect by indomethacin supplement may suggest that vitamin C exert its effect via alteration of arachidonic acid metabolism.

• Tuberculosis and Respiratory Diseases
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• v.46 no.3
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• pp.317-326
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• 1999

Background: Neural control of airway function is through parasympathetic, sympathetic and non-adrenergic, non-cholinergic mechanisms. The autonomic nervous system controls the airway smooth muscle tone, mucociliary system, permeability and blood flow in the bronchial circulation and release of mediators from the mast cells and other inflammatory cells. The cardiovascular and respiratory autonomic efferent fibers have a common central origin, so altered cardiovascular autonomic reflexes could reflect the altered respiratory autonomic status. Therefore, we performed this study to assess the autonomic abnormality and determine the correlating factors of severity of autonomic neuropathy in patients with chronic obstructive pulmonary disease(COPD) using easily reproducible cardiovascular autonomic reflex function test. Method: The study included 20 patients with COPD and 20 healthy persons obtained on Health Promotion Center in Yeungnam university hospital. All the patients had history and clinical features of COPD as defined by the American Thoracic Society. Any patients with myocardial ischemia, cardiac arrythmia, hypertension, central or peripheral nervous system disease, diabetes mellitus, or any other diseases known to produce autonomic neuropathy, has excluded. The autonomic nervous system function tests included three tests evaluating the parasympathetic system and two tests evaluating the sympathetic system. And also all subjects were subjected to pulmonary function test and arterial blood gas analysis. Results: Autonomic dysfunction was more commonly associated with patients with COPD than healthy person The parasympathetic dysfunction was frequent in patient with COPD, but sympathetic dysfunction seemed preserved. The severity of parasympathetic dysfunction in patients with COPD was correlated with the degree of duration of disease, smoking, reductions in the value of $FEV_1$ and FVC, and arterial hypoxemia but no such correlation existed for age, type of COPD, $FEV_1$/FVC, or $PaCO_s$. Conclusion: There is high frequency of parasympathetic dysfunction associated with COPD and the parasympathetic abnormality in COPD is increased in proportion to severity of airway disease. In COPD, parasympathetic dysfunction probably does not the cause of disease, but it may be an effect of disease progression.

• Clinical and Experimental Pediatrics
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• v.51 no.8
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• pp.879-885
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• 2008

Purpose : The human lung fibroblast may act as an immunomodulatory cell by providing pro-inflammatory cytokines and chemokines, which are important in airway remodeling. Vascular endothelial growth factor (VEGF) induces mucosal edema and angiogenesis. Thymus and activation regulated chemokine (TARC) induces selective migration of T helper 2 cells. We investigated whether human lung fibroblasts produced VEGF and TARC, and the effects were augmented with the co-culture of fibroblasts and human bronchial smooth muscle cells (HBSMC), and whether dexamethasone can inhibit the proliferation and the release of VEGF in lung fibroblasts. Methods : Human lung fibroblasts were cultured with and without HBSMC, growth-arrested in serum-deprived medium, and pretreated with dexamethasone for 16 hours. After 24-hour stimulation with platelet derived growth factor-BB (PDGF-BB) and/or transforming growth factor-${\beta}$ (TGF-${\beta}$), culture supernatant was harvested for assays of VEGF and TARC. Cell proliferation was assayed using BrdU cell proliferation ELISA kit. Results : 1) The release of VEGF was significantly increased after stimulation with TGF-${\beta}$, and its release was augmented when co-stimulated with PDGF and TGF-${\beta}$. 2) VEGF release induced by PDGF or TGF-${\beta}$ was inhibited by dexamethasone. 3) There was no synergistic effect on the release of VEGF when human lung fibroblasts were co-cultured with HBSMC. 4) Dexamethasone did not suppress human lung fibroblasts proliferations. 5) Neither TGF-${\beta}$ nor PDGF induced TARC release from lung fibroblasts. Conclusion : Human lung fibroblasts may modulate airway remodeling by release of VEGF, but they have no synergistic effects when co-cultured with HBSMC. Dexamethasone suppresses VEGF release, not proliferation of lung fibroblast.

• Tuberculosis and Respiratory Diseases
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• v.49 no.1
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• pp.37-48
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• 2000

Backgrounds : The pathophysiology of chronic airflow obstruction, such as bronchial asthma, is characterized by mucus hypersecretion, goblet cell hyperplasia(GCH), smooth muscle hypertrophy, and inflammatory cells infiltration. In fatal asthma patients, one distinct findings is mucus hypersecretion due to GCH. However, the mechanisms of GCH in these hypersecretory diseases remain still unknown. In this study, a rat model was rapidly induced with GCH by instillation of $TiO_2$, intratracheally. We intend to confirm GCH and association of concomitant inflammatory cells infiltration and to observe the effect of potent antiinflammatory agent, that is dexamethasone, on GCH with inflammatory cells. Methods : Twenty-one 8-weeks-old male Sprague-Dawley rats were divided into three groups. Endotoxinfree water was instilled intratracheally in group 1(control) ; $TiO_2$, was instilled in the group 2 ; and dexamethasone was injected intraperitoneally to group 3 before $TiO_2$ instillation. After 120 hours, all rats were sacrificed, and trachea, bronchi, and lungs were resected respectively. These tissues were made as paraffin blocks and stained as PAS for goblet cells and Luna stain for eosinophils. We calculated the ratio of goblet cell to respiratory epithelium and number of infiltrated eosinophils from each tissue. Results : (1) Fraction of goblet cells was significantly increased in group 2 than in group 1 in the trachea and in the main bronchus. (10.19$\pm$11.33% vs 4.09$\pm$8.28%, p<0.01 and 34.09$\pm$23.91% vs 3.61$\pm$4.84%, p<0.01, respectively). (2) Eosinophils were significantly increased in the airway of group 2 than that of group 1. (5.43$\pm$3.84% vs 0.17$\pm$0.47 in trachea and 47.71$\pm$16.91 vs 2.71$\pm$1.96 in main bronchi). (3) There was a positive correlation between goblet cells and eosinophils(r=0.719, p=0.001). (4) There was significant difference in the decrease of goblet cells after dexamethasone injection between group 2 and group 3 (p<0.01). Also, infiltration of eosinophils was suppressed by dexamethasone. Conclusion : We made an animal model of $TiO_2$-induced goblet cell hyperplasia. GCH was observed mainly in the main bronchi with concomitant eosinophilic infiltration. Both goblet cell hyperplasia and eosinophilic infiltration were suppressed by dexamethasone. This animal model may serve as a useful tool in understanding of the mechanism of GCH in chronic airway diseases.

• Tuberculosis and Respiratory Diseases
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• v.49 no.4
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• pp.486-494
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• 2000

Background : The dominant innervation of airway smooth muscle is parasympathetic fibers which are carried in the vagus nerve. Activation of these cholinergic nerves releases acetylcholine which binds to $M_3$ muscarinic receptors on the smooth muscle causing bronchocontraction. Acetylcholine also feeds back onto neuronal $M_2$ muscarinic receptors located on the postganglionic cholinergic nerves. Stimulation of these receptors further inhibits acetylcholine release, so these $M_2$, muscarinic receptors act as autoreceptors. Loss of function of these $M_2$ receptors, as it occurs in animal models of hyperresponsiveness, leads to an increase in vagally mediated hyperresponsiveness. However, there are limited data pertaining to whether there are dysfunctions of these receptors in patients with asthma. The aim of this study is to determine whether there are dysfunction of $M_2$ muscarinic receptors in asthmatic patients and difference of function of these receptors according to severity of asthma. Method : We studied twenty-seven patients with asthma who were registered at Pulmonology Division of Korea University Hospital. They all met asthma criteria of ATS. Of these patients, eleven patients were categorized as having mild asthma, eight patients moderate asthma and eight patients severe asthma according to severity by NAEPP Expert Panel Report 2(1997). All subjects were free of recent upper respiratory tract infection within 2 weeks and showed positive methacholine challenge test ($PC_{20}$<16mg/ml). Methacholine provocation tests were performed twice on separate days allowing for an interval of one week. In the second test, pretreatment with the $M_2$ muscarinic receptor agonist pilocarpine($180{\mu}g$) through inhalation was performed be fore the routine procedures. Results : Eleven subjects with mild asthma and eight subjects with moderate asthma showed significant increase of $PC_{20}$ from 5.30$\pm$5.23mg/ml(mean$\pm$SD) to 20.82$\pm$22.56mg/ml(p=0.004) and from 2.79$\pm$1.51mg/ml to 4.67$\pm$3.53mg/ml(p=0.012) after pilocarpine inhalation, respectively. However, in the eight subjects with severe asthma significant increase of $PC_{20}$ from l.76$\pm$1.50mg/ml to 3.18$\pm$4.03mg/ml(p=0.161) after pilocarpine inhalation was not found. Conclusion : In subjects with mild and moderate asthma, function of $M_2$ muscarinic receptors was normal, but there was a dysfunction of these receptors in subjects with severe asthma. ηlese results suggest that function of $M_2$ muscarinic receptors is different according to severity of asthma.