• Tuberculosis and Respiratory Diseases
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• v.53 no.5
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• pp.519-529
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• 2002

Background : The therapeutic effects of surfactants on acute lung injury derive not only from their recruiting action on collapsed alveoli but also from their anti-inflammatory action in the alveolar sapce. This study evaluated the anti-inflammatory action of a surfactant in an acute lung injury model of rats by neutrophils were recollected from the BAL fluid and the NF-${\kappa}B$ activity of the neutrophilic nuclear protein was evaluated. Methods : Male Sprague-Dawley rats weighing approximately 300 gram were divided into 3 groups, which consisted of 6 rats respectively. In the control group, normal saline(3ml/kg) was instilled into the trachea twice with 30 minute interval. In two other groups, acute lung injury was induced by the intra-tracheal instillation of LPS(5mg/kg). Thirty minutes later, either a surfactant(ST group; 30mg/kg) or normal saline(NT group: 3ml/kg) was instilled via the trachea. Twenty-four hours after the LPS instillation, the BAL fluid was retrieved to measure the WBC count and cytokine(IL-$1{\beta}$ and IL-6) levels. The neutrophils were isolated from the BAL fluid and the nuclear protein was extracted to evaluate the NF-${\kappa}B$ activity using a eletrophoretic mobility shift assay(EMSA). Results : The WBC count of the BAL fluid of the ST group($3,221{\pm}1,914{\times}10^3/{\mu}l$) was higher than that of the control group($356{\pm}275{\times}10^3/{\mu}l$)(p<0.05) and lower than that of the NT group($5,561{\pm}1,757{\times}10^3/{\mu}l$)(p<0.05)). The BAL fluid level of IL-$1{\beta}$ from the NT group($2,064{\pm}1,082pg/ml$) was higher than those of the ST group($360{\pm}234pg/ml$)(p<0.05) and the control group(0pg/ml)p<0.05) and control group($49{\pm}62pg/ml$)(p<0.05). The NF-${\kappa}B$ activity of the neutrophilic nuclear protein in the ST group and NT group was similar. Conclusion : The surfactant, attenuates the alveolar inflammation in the acute lung injury of rats model. However, its anti-inflammatory action does no't appear to be mediated by the inhibition of NF-${\kappa}B$ activity.

• Clinical and Experimental Pediatrics
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• v.46 no.12
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• pp.1200-1206
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• 2003

Purpose : This study was conducted for the use of nasal continuous positive airway pressure (CPAP), by comparing the early use of non-invasive nasal CPAP with low intermittent mandatory ventilation(low IMV) and endotracheal CPAP in weaning a mechanical ventilator from infants with moderate respiratory distress syndrome(RDS). Methods : Thirty infants in the study group, with moderate RDS from November 2001 to June 2002, were administered surfactants and treated with the mechanical ventilator, and applied the nasal CPAP in weaning. Thirty infants of the control group, from January 1999 to September 2001, were applied low IMV and endoctracheal CPAP in weaning. Results : There were no significant differences in the characteristics, the severity of clinical symptoms, the initial laboratory findings and settings of the mechanical ventilator. After weaning, the study group showed no significant changes in $PaCO_2$. However, the control group showed a slight $CO_2$ retension after one and 12 hours. Twenty eight infants(93.3%) of the study group and 24 infants(80%) of the control group were successfully extubated. The primary cause of failure was apnea. There were no significant differences in the duration of weaning and the mechanical ventilator treatment between the groups. Complications in weaning were related to the fixation of nasal CPAP and the mechanical problems caused by endotracheal tube. Conclusion : Aggressive weaning is possible for moderate RDS, in which the nasal CPAP was used without the low IMV and the endotracheal CPAP process. It had no difficulties. In conclusion, the nasal CPAP is an adequate weaning method for moderate RDS.

• Tuberculosis and Respiratory Diseases
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• v.43 no.1
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• pp.63-68
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• 1996

Background: Interferon-$\gamma$ has various biologic effects, including antiviral effect, antitumor proliferative effect, activation of macrophage and B lymphocyte, and increased expression of major histocompatibility complex. Especially, antitumor proliferative effect of interferon-$\gamma$ has already been proved to be important in vivo as well as in vitro. And, clinical studies of interferon-$\gamma$ have been tried in lung cancer patients. However, the mechanism of antitumor effect of interferon-$\gamma$ has not yet been established despite of many hypotheses. "Necrosis" is a type of cell death which is well known to occur in the circumstances of severe stresses. In contrast, "apoptosis" is another type of cell death which occurs in such biological circumstances as embryonic development, regression of organs, and self-tolerance of lymphocytes. And, apoptosis is an active process of cell death in which cells are dying with fragmentations of their cytoplasms and nuclei. And, in the process of apoptosis the DNAs of cells are cleaved between nucleosomes by unidentified endonuclease and therefore DNAs of apoptotic cells result in a typical electrophoresis pattern known as DNA ladder pattern. Recently it has been suggested that cytotoxic effect of interferon-$\gamma$ occurs via apoptosis. To elucidate the mechanism of antitumor cytotoxic effect of interferon-$\gamma$, we microscopically observed a lung cancer cell line, A549 which was treated with interferon-$\gamma$. We observed A545 treated with interferon-$\gamma$ was dying fragmented. And so, we performed this study to find out that the mechanism of antitumor cytotoxic effect of interferon-$\gamma$ be apoptosis. Method: We treated A549, human lung cancer cell line with various concentration of interferon-$\gamma$ and quantified its cytotoxic effect of various periods, 24 hours, 72 hours and, 120 hours by MTT(dimethylthiazolyl diphenyltetrazolium bromide) bioassay. Also, after we treated A549 with 100 units/mi of interferon-$\gamma$ for 120 hours, we observed the pattern of cell death with inverted microscope and we extracted DNAs from the dead A549 cells and observed the pattern of 1.5% agarose gel electrophoresis with ethidium bromide staining. Result: 1) Cytotoxic effect of interferon-$\gamma$ on A549: For the first 24 hours, threre was little cytotoxic effect and for between 24 hours and 72 hours, there was the beginning of cytotoxic effect and for 120 hours there was increased cytotoxic effect. 2) Pattern of A549 cell death by interferon-$\gamma$: We observed with inverted microscope that A549 cells were dying fragmented. 3) DNA ladder pattern of gel electrophoresis: We observed DNA ladder pattern of gel electrophoresis of extracted DNAs from dead A549 cells. Conclusion: We concluded that the mechanism of interferon-$\gamma$induced cytotoxicity on lung cancer cell line, A549 be via apoptosis.

• Tuberculosis and Respiratory Diseases
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• v.40 no.3
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• pp.236-249
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• 1993

Background: Among the injurious agents to which the lung airspaces are constantly exposed are reactive species of oxygen. It has been widely believed that reactive oxygen species may be implicated in the etiology of lung injuries. In order to elucidated how this oxidant causes lung cell injury, we investigated the effects of exogenous $H_2O_2$ on alveolar epithelial barrier characteristics. Methods: Rat type II alveolar epithelial cells were plated onto tissue culture-treated polycarbonate membrane filters. The resulting confluent monolayers on days 3 and 4 were mounted in a modified Ussing chamber and bathed on both sides with HEPES-buffered Ringer solution. The changes in short-circuit current (Isc) and monolayer resistance (R) in response to the exogenous hydroperoxide were measured. To determine the degree of cellular catalase participation in protection against $H_2O_2$ injury to the barrier, experiments were repeated in the presence of 20 mM aminotriazole (ATAZ, an inhibitor of catalase) in the same bathing fluid as the hydroperoxide. Results: These monolayers have a high transepithelial resistance (>2000 ohm-$cm^2$) and actively transport $Na^+$ from apical fluid. $H_2O_2$(0-100 mM) was then delivered to either apical or basolateral fluid. Resulting indicated that $H_2O_2$ decreased Isc and R gradually in dose-dependent manner. The effective concentration of apical $H_2O_2$ at which Isc (or R) was decreased by 50% at one hour ($ED_{50}$) was about 4 mM. However, basolateral $H_2O_2$ exposure led to $ED_{50}$ for Isc (and R) of about 0.04 mM. Inhibition of cellular catalase yielded $ED_{50}$ for Isc (and R) of about 0.4 mM when $H_2O_2$ was given apically, while $ED_{50}$ for basolateral exposure to $H_2O_2$ did not change in the presence of ATAZ. The rate of $H_2O_2$ consumption in apical and basolateral bathing fluids was the same, while cellualr catalase activity rose gradually with time in culture. Conclusion: Our data suggest that basolateral $H_2O_2$ may affect directly membrane component (e.g., $Na^+,\;K^+$-ATPase) located on the basolateral cell surface. Apical $H_2O_2$, on the other hand, may be largely degraded by catalase as it passes through the cells before reaching these membrane components. We conclude that alveolar epithelial barrier integrity as measured by Isc and R are compromised by $H_2O_2$ being relatively sensitive to basolateral (and insensitive to apical) $H_2O_2$.

• Tuberculosis and Respiratory Diseases
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• v.47 no.5
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• pp.601-608
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• 1999

Background: Tuberculous pleural effusion responds well to the anti-tuberculosis agents in general, so no further aggressive therapeutic managements to drain the tuberculous effusion is necessary except in case of diagnostic thoracentesis. But in clinical practice, we often see some patients who later decortication need due to dyspnea caused by pleural thickening despite the completion of anti-tuberculosis therapy in the patients with tuberculous effusion. Especially, the patients with loculated tuberculous effusion might have increased chance of pleural thickening after treatment. The purpose of this study was that intrapleural urokinase instillation could reduce the pleural thickening in the treatment of loculated tuberculous pleural effusion. Methods: Thirty-seven patients initially diagnosed as having loculated tuberculous pleural effusion were randomly assigned to receive either the combined treatment of urokinase instillation and anti-tuberculosis agents(UK group) and anti-tuberculosis agents(Non-UK group) alone. The 16 patients in UK group received a single radiographically guided pig-tail catheter ranging in size from 10 to 12 French. 100,000 units of urokinase was dissolved in 150 ml of normal saline and instilled into the pleural cavity via pig-tail catheter every day, also this group was treated with anti-tuberculosis agents. While the 21 patients in Non-UK group were treated with anti-tuberculosis agents only except diagnostic thoracentesis. Then we evaluated the residual pleural thickening after treatment for their loculated tuberculous pleural effusion between the two groups. Also the duration of symptoms and the pleural fluid biochemistry like WBC counts, pH, lactic dehydrogenase(LDH), glucose, proteins, and adenosine deaminase(ADA) were compared. Results: 1) The residual pleural thickening(RPT)($5.08{\pm}6.77$ mm) of UK group was significantly lower than that($20.3222{\pm}26.37$ mm) of Non-UK group(P<0.05). 2) The duration of symptoms before anti-tuberculosis drug therapy of patients with RPT$\geq$10 mm($5.23{\pm}3.89$ wks) was significantly longer than the patients with RPT<10 mm($2.63{\pm}1.99$ wks)(P<0.05). 3) There were no significant differences in the pleural fluid findings like WBC count, glucose, LDH, proteins, pH, ADA between the patients with RPT$\geq$10 mm and the patients with RPT<10 mm. Conclusion : The treatment of loculated tuberculous pleural effusion with the urokinase instillation via percutaneous transthoraic catheter was effective to reduce the pleural thickening.

• Tuberculosis and Respiratory Diseases
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• v.46 no.5
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• pp.685-696
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• 1999

Background : Idiopathic pulmonary fibrosis (IPF) is a diffuse inflammatory and fibrosing process that occurs within the interstitium and alveolus of the lung with invariably poor prognosis. The major problem in management of IPF results from the variable rate of disease progression and the difficulties in predicting the response to therapy. The purpose of this retrospective study was to evaluate the short-term efficacy of steroid and immunosuppressive therapy for IPF and to identify the pre-treatment determinants of favorable response. Method : Twenty patients of IPF were included. Diagnosis of IPF was proven by thoracoscopic lung biopsy and they were presumed to have active progressive disease. The baseline evaluation in these patients included clinical history, pulmonary function test, bronchoalveolar lavage (BAL), and chest high resolution computed tomography (HRCT). Fourteen patients received oral prednisolone treatment with initial dose of 1mg/kg/day for 8 to 12 weeks and then tapering to low-dose prednisolone (0.25mg/kg/day). Six patients who previously had experienced significant side effects to steroid received 2mg/kg/day of oral cyclophosphamide with or without low-dose prednisolone. Follow-up evaluation was performed after 6 months of therapy. If patients met more than one of followings, they were considered to be responders : (1) improvement of more than one grade in dyspnea index, (2) improvement in FVC or TLC more than 10% or improvement in DLco more than 20% (3) decreased extent of disease in chest HRCT findings. Result : One patient died of extrapulmonary cause after 3 month of therapy, and another patient gave up any further medical therapy due to side effect of steroid. Eventually medical records of 18 patients were analyzed. Nine of 18 patients were classified into responders and the other nine patients into nonresponders. The histopathologic diagnosis of the responders were all nonspecific interstitial pneumonia (NSIP) and that of nonresponders were all usual interstitial pneumonia (UIP) (p<0.001). The other significant differences between the two groups were female predominance (p<0.01), smoking history (p<0.001), severe grade of dyspnea (p<0.05), lymphocytosis in BAL fluid ($23.8{\pm}16.3%$ vs $7.8{\pm}3.6%$, p<0.05), and less honeycombing in chest HRCT findings (0% vs $9.2{\pm}2.3%$, p<0.001). Conclusion : Our results suggest that patients with histopathologic diagnosis of NSIP or lymphocytosis in BAL fluid are more likely to respond to steroid or immunosuppressive therapy. Clinical results in large numbers of IPF patients will be required to identify the independent variables.

• Tuberculosis and Respiratory Diseases
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• v.41 no.2
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• pp.87-96
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• 1994

Background : Since tumor necrosis factor was discovered in 1975, TNF has been well known about its cytotoxic effect on tumor cells in vivo and in vitro. According to the recent improvement of molecular biological techinques, it is possible that exogenous TNF gene is transferred to tumor cells and is expressed in theirs. By virtue of TNF gene transfer, we have expected that TNF expressed in TNF-gene-transferred tumor cells would kill tumor cells in vivo without systemic side effect. The expected mechanisms in which antitumor effects of TNF expressed in TNF-gene-transferred tumor cells are working would be as followings. In the first mechanism, TNF expressed in TNF-gene-transferred tumor cells would kill tumor cells around(like homicide). In the second mechanism, TNF expressed in TNF-gene-transferred tumor cells would kill themselves(like suicide). In the third mechanism, TNF expressed in TNF-gene-transferred tumor cells would recruit immune effector cells and kill tumor cells indirectly. In the last mechanism, TNF expressed in TNF-gene-transferred tumor cells would augment cytokine such as interferon-$\gamma$ to kill tumor cells. Among these four mechanisms of antitumor effect, only the second mechanism has not been established yet. Therefore, to elucidate the second mechanism, We performed this study. Method : We transferred TNF-$\alpha$ gene to NCI-H2058, a human mesothelioma cell line and WEHI164, a murine fibrosarcoma cell line by using retroviral vector(pLT12SNTNF). And, We determined by using MTT assay whether TNF expressed in TNF-gene-transferred tumor cell lines would kill themselves like suicide or not. Then, if TNF-gene-transferred tumor cell lines would not suicide themselves, I would know more about the TNF sensitivity of TNF-gene-transferred tumor cell lines to exogenous TNF also by MTT assay. Result : NCI-H2058 and WEHI164 which were sensitive to TNF, became far less sensitive to endogenous and exogenous TNF after being transferred TNF-$\alpha$ gene to. Conclusion : TNF-gene-transfer to NCI-H2058 and WEHI164 gave them resistance to TNF.

• 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.41 no.3
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• pp.231-238
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• 1994

Backgroud: Since the demonstration of the fact that vascular relaxation by acetylcholine(Ach) results from the release of relaxing factor from the endothelium, the identity and physiology of this endothelium-derived relaxing factor(EDRF) has been the target for many researches. EDRF has been identified as nitric oxide(NO). With the recent evidences that EDRF is an important mediator of vascular tone, there have been increasing interests in defining the role of the EDRF as a potential mediator of hypoxic pulmonary vasoconstriction. But the role of EDRF in modulating the pulmonary circulation is not compeletely clarified. To investigate the endothelium-dependent pulmonary vasodilation and the role of EDRF during hypoxic pulmonary vasoconstriction, we studied the effects of $N^G$-monomethyl-L-arginine(L-NMMA) and L-arginine on the precontracted pulmonary arterial rings of the rat in normoxia and hypoxia. Mothods: The pulmonary arteries of male Sprague Dawley(300~350g) were dissected free of surrounding tissue, and cut into rings. Rings were mounted over fine rigid wires, in organ chambers filled with 20ml of Krebs solution bubbled with 95 percent oxygen and 5 percent carbon dioxide and maintained at $37^{\circ}C$. Changes in isometric tension were recorded with a force transducer(FT.03 Grass, Quincy, USA) Results: 1) Precontraction of rat pulmonry artery with intact endothelium by phenylephrine(PE, $10^{-6}M$) was relaxed completely by acetylcholine(Ach, $10^{-9}-10^{-5}M$) and sodium nitroprusside(SN, $10^{-9}-10^{-5}M$), but relaxing response by Ach in rat pulmonary artery with denuded endothelium was significantly decreased. 2) L-NMMA($10^{-4}M$) pretreatment inhibited Ach($10^{-9}-10^{-5}M$)-induced relaxation, but L-NMMA ($10^{-4}M$) had no effect on relaxation induced by SN($10^{-9}-10^{-5}M$). 3) Pretreatment of the L-arginine($10^{-4}M$) significantly reversed the inhibition of the Ach ($10^{-9}-10^{-5}M$)-induced relaxation caused by L-NMMA($10^{-4}M$) 4) Pulmonary arterial contraction by PE($10^{-6}M$) was stronger in hypoxia than normoxia but relaxing response by Ach($10^{-9}-10^{-5}M$) was decreased, 5) With pretreatment of L-arginine($10^{-4}M$), pulmonary arterial relaxation by Ach($10^{-9}-10^{-5}M$) in hypoxia was reversed to the level of relaxation in normoxia. Conclusion: It is concluded that rat pulmonary arterial relaxation by Ach is dependent on the intact endothelium and is largely mediated by NO. Acute hypoxic pulmonary vasoconstriction is related to the suppression on NO formation in the vascular endothelium.

• Tuberculosis and Respiratory Diseases
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• v.45 no.6
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• pp.1143-1153
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• 1998

Background : Recent outbreaks of pulmonary disease due to drug-resistant strains of Mycobacterium Tuberculosis have resulted in significant morbidity and mortality in patients worldwide. We reviewed our experience to evaluate the effects of pulmonary resection on the management of multidrug-resistant tuberculosis. Method : A retrospective review was performed of 41 patients undergoing pulmonary resection for multidrug-resistant tuberculosis between January 1993 and December 1997. We divided these into 3 groups according to the radiologic findings : (1) patients who have reasonably localized lesion (Localized Lesion Group ; LLG) (2) patients who have cavitary lesions after pulmonary resection on chest roentgenogram (Remained Cavity Group : RCG) (3) patients who have Remained infiltrative lesions postoperatively (Remained infiltrative group : RIG). We evaluated the negative conversion rate after resection and overall response rate of the groups. Then they were compared with the results of the chemotherapy on the multi drug-resistant tuberculosis which has been outcome by Goble et al. Goble et al reported that negative conversion rate was 65% and overall response rate, 56% over a mean period of 5.1 months. Results : Seventy five point six percent were men and 24.4% women with a median age of 31 years (range, 16 to 60 years). Although the patients were treated preoperatively with multidrug regimens in an effort to reduce the mycobacterial burden, 22 of 41 were still sputum culture positive at the time of surgery. 20 of 22 patients(90.9%, p<0.01) responded which is defined as negative sputum cultures within 2 months postoperative. Of 26 patients with the sufficient follow up data, 19 have Remained sputum culture negative for a mean duration of 25.7 months (73.1%, p<0.05). The bulk of the disease was manifest in one lung, but lesser amounts of contralateral disease were demonstrated in 15, consisted of 8 in RIG and 7 in RCG, of 41. 12 of 12 patients (100%, p<0.01) who were sputum positive at the time of surgery in LLG converted successfully. 14 of 15 patients (93.3%, p<0.05) with the follow up have completed treatment and not relapsed for a mean period of 25. 7 months. The mean length of postoperative drug therapy of LLG was 12.2 months. In RIG, postoperative negative conversion rate was 83.3% which was not significant statistically. There was a statistical significance in overall response rate (100%, p<0.05) of RIG for a mean period of 24.4 months with a mean length of postoperative chemotherapy, 11.8 months. In RCG a statistically lower overall response rate (14.3%, p<0.01) has been revealed for a mean duration of follow up, 24.2 months. A negative conversion rate of RCG was 75% which was not significant statistically. Conclusion : Surgery plays an important role in the management of patients with multidrug-resistant Mycobacterium tuberculosis infection. Aggressive pulmonary resection should be performed for resistant Mycobacterium tuberculosis infection to avoid treatment failure or relapse. Especially all cavitary lesions on preoperative chest roentgenogram should be resected completely. If all of them could not be resected perfectly, you should not open the thorax.