• Tuberculosis and Respiratory Diseases
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• v.45 no.3
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• pp.553-564
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• 1998

Background: The immediate hoot response to LPS is the production of proinflammatory cytokines that act as intercellular mediators in inflammatory reactions, including acute lung injury. These "early response" cytokines transmit signals from recognition cells to target or effector cells. This host response is further amplified by the expression of leukocyte chemoattractants, growth factors, and adhesion molecules, resulting in an array of proinflammatory events. This experiment was performed to define the lung origin of proinflammatory cytokines, such as TNF-$\alpha$, IL 6 in early periods of endotoxin induced acute lung injury (ALI). Method: The healthy male Sprague-Dawley, weighted 150 - 250g, were divided into saline control (NC) and endotoxemia-induced ALI (ETX-), and leukopenic endotoxemia-induced ALI (CPA-ETX-Group) which was induced by cyclophosphamide, 70 mg/kg i.p. injection. Acute lung injury was evoked by LPS, 5 mg/kg, intravenously administered. Bronchoalveolar lavage was performed at 0, 3, 6 h after LPS-treated to estimate the influx of phagocytes and concentration of total protein, and cytokines as TNF-$\alpha$ and IL 6 by a bioassy using MIT method. We also examined the localization of TNF-$\alpha$ and IL 6 protein in endotoxemia-challenged lung tissue by immunohistochemical stain (IH). Results: The total cell, macrophage and PMN count in BALF were elavated in ETX group compared to NC(p<0.05). In CPA-ETX group, total cell and macrophage count in BALF were not changed compared to NC. but PMN count was markedly reduced and it took part in less than 0.1 % of total BAL cells (p<0.01). The protein concentration in BALF were significantly increased in ETX and CPA-ETX group Compared to NC (p<0.05), but there was significant difference between ETX- and CPA-ETX group only at 6 h (p<0.05). This observation suggested that even if PMNs are involved in the pathogenesis of acute lung injury, their role cannot be viewed as essential The concentration of TNF-$\alpha$ and IL 6 in BALF was significantly increased in the ETX- and CPA-ETX group compared to NC. There was no difference between ETX- and CPA-ETX group. In IH, anti-TNF-$\alpha$- and anti-IL 6 antibody was strongly localized at interstitial monocytes and alveolar macrophages in endotoxemia-challenged lung tissue. From above point of view, activated alveolar macrophage/monocyte considered as a prominent source of proinflammatory cytokines in endotoxemia-challenged lung injury. Conclusion: The prominent source of proinflammatory cytokines in early periods of endotoxemia-induced lung injury will be the activated resident macrophages like an alveolar macrophage and interstitial monocytes. The pulmonary macrophage/monocyte will impact the initiation and continuance of lung injury without PMNs's certain inflammatory role, particularly in endotoxemia-induced acute lung injury.

• 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.

• Journal of Chest Surgery
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• v.36 no.8
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• pp.545-558
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• 2003

Adult respiratory distress syndrome (ARDS) is of particular interest because of its severity of the associated lung injury and its high mortality. However, the pathophysiologies of ARDS in infant and childhood groups are still not well clarified inspite of many previous investigations. To investigate the time course of pathophysiology of ARDS in infant and childhood groups, this study was designed with experimental endotoxin-induced ARDS model using young rabbits (8 week-old). Material and Method: Rabbits were divided into the control group (n=8) and the endotoxin-treated group (n=32). The endotoxin group was subdivided into 4 groups by the sampling times as 3, 6, 12 and 24 hr-groups (G- $E_{3,6,12,24,}$ each n=8). The experimental ARDS was made by a bolus injection of endotoxin (Escherichia coli serotype 055 : B5, 0.50 mg/kg) via rabbit ear vein. For evaluation of the hematologic and inflammatory markers, and superoxide dismutase (SOD) concentrations, the blood samples were taken from the heart. The bronchoalveolar lavage fluid (BALF) were obtained for analysis of the leukocytes and protein concentration. With biopsy of the lung, histopathologic changes of the lung were also evaluated. Result: In the endotoxin groups, significant leukopenia (owing to pancytopenia) occurred in 3 and 6-hr groups, which was followed by significant leukocytosis (owing to neutrophilia) in the 12 and 24-hr groups (p<0.05). Serum levels of tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and interleukin-1 $\beta$ (IL-1 $\beta$) in the endotoxin groups were higher than those of control group (p<0.05). Serum levels of superoxide dismutase (SOD) of G- $E_{3}$ and G- $E_{6}$ were higher than those of control group, whereas those of G- $E_{12}$ were lower than those of control groups (p<0.05). Total leukocyte counts and protein con-centrations in BALF were significantly elevated in the endotoxin groups compared to the control group (p < 0.05). The hemorrhagic pattern of BALF showed occurred in the endotoxin groups. The endotoxin groups (in G- $E_{6}$) had severe infiltration of inflammatory cells (lymphocyte and monocyte) in the pulmonary interstitium and parenchyma, migrations of neutrophil and eosinophil into alveolar spaces and interstitial widening, which are the evidences of acute lung injury. In the endotoxin groups, there were significant positive correlations between the BALF findings and the immunologic markers (TNF-$\alpha$, IL-1$\beta$, SOD) (p<0.05). Conclusion: Severe acute lung injury occurred in all the endotoxin-treated rabbits. The pathophysiologic findings were so progressive until 6-hr by time dependant pattern, and then recovered slowly, Variable hematologic, immuno-logic, and pathologic factors were well correlated in the development and progression of endoxin-induced lung injury. The pathophysiologic responses were sensitive and rapid in young rabbit Young rabbit seemed to be a useful experimental animal model for infant and childhood groups.roups.

• Tuberculosis and Respiratory Diseases
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• v.48 no.4
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• pp.530-542
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• 2000

Background : Nonspecific interstitial pneumonia (NSIP) has been reported recently to have shown much better response to medical treatment and better prognosis compared with idiopathic UIP. However, clinical characteristics of idiopathic NSIP discriminating it from UIP have not been clearly defined. Method : Among 120 patients with biopsy-proven diffuse interstitial lung diseases admitted to the Samsung Medical Center between July 1996 and March 2000, 18 patients with idiopathic NSIP were included in this study. Retrospective chart review and radiographic analysis were performed. Results : 1) At diagnosis, 17 patients were female and the average age was $55.2{\pm}8.4$ years (44~73 years). The average duration from development of respiratory symptom to surgical lung biopsy was $9.9{\pm}17.1$ months. Increase in bronchoalveolar lavage fluid lymphocytes ($23.0{\pm}13.1%$) was noted. On HRCT, ground glass and irregular linear opacity were observed, but honeycombing was absent in all patients. 2) Corticosteroids were initially given to 13 patients, but the medication was stopped in 3 patients due to severe side effects. Further medical therapy was not possible in 1 patient who experienced streroid-induced psychosis. Herpes zoster (n=3), tuberculosis (n=1), avascular necrosis of the hip (n=1), cataract (n=2) and diabetes mellitus (n=1) developed during prolonged corticosteroid administration. Of the 7 patients receiving oral cyclophosphamide therapy, hemorrhagic cystitis hindered one patient from continuing with the medication. 3) After medical treatment, 14 of 17 patients improved, and 3 patients remained stable (mean follow-up ; $24.1{\pm}11.2$ months). FVC increased by $20.2{\pm}11.2%$ of predicted value and the extent of ground glass opacity on HRCT decreased significantly ($15.7{\pm}14.7%$). 4) Of the 14 patients who had stopped medication, 5 showed recurrence of NSIP and 2 became aggravated during steroid tapering. All patients with recurrence showed deterioration within one year after completion of initial treatment. Conclusion : Since idiopathic NSIP has unique clinical profiles and shows good prognosis, diagnosis different from UIP, and aggressive medical treatment are needed.

• Tuberculosis and Respiratory Diseases
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• v.48 no.6
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• pp.932-943
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• 2000

Background : Nonspecific interstitial pneumonitis (NSIP) is most likely to be confused with usual interstitial pneumonitis (UIP). Unlike patients witþ UIP, the majority of patients with NSIP have a good prognosis, with most patients improving after treatment with corticosteroids. Therefore it is clinically important to differentiate NSIP from UIP. Up to now, the only means of differentiating these two diseases was by means of surgical lung biopsy. American Thoracic Society (ATS) proposed a clinical diagnostic criteria for UIP to provide assistance to clinicians in its diagnosis without surgical lung biopsy. This study is aimed to investigate whether there were clinical and radiological differences between NSIP and UIP, and the usefulness of ATS clinical diagnostic criteria for UIP in Korea. Methods : We studied 60 patients with UIP and NSIP confirmed by surgical lung biopsy. Clinical manifestations, pulmonary function test, arterial blood gas analysis, bronchoalveolar lavage (BAL), and high resolution computed tomography (HRCT) were evaluated and analyzed by Chi-square test or t-test. The clinical criteria for UIP proposed by ATS were applied to all patients with idiopathic interstitial pneumonia. Results : Forty-two patients with UIP and 18 with NSIP were pathologically identified. Among the 18 patients with NSIP (M : F=1 : 17), the mean age was 55.2$\pm$8.4 (44~73) yr. Among the 42 patients with UIP (M : F=33 : 9), the mean age was 59.5$\pm$7.1 (45~74) yr (p=0.046). Fever was more frequent in NSIP (39%) (p=0.034), but clubbing was frequently observed in UIP (33%) (p=0.023). BAL lymphocytosis was more frequent (23%) (p=0.0001) and CD4/CD8 ratio was lower in NSIP (p=0.045). On HRCT, UIP frequently showed honeycomb appearance (36 of 42 patients) though not in NSIP (p=0.0001). Six of 42 UIP patients (14.3%) met the ATS clinical criteria for IPF, and 3 of 16 NSIP patients (18.8%) met the diagnostic criteria. Conclusion : Being a relatively young female and having short duration of illness, fever, BAL lymphocytosis, low CD4/CD8 ratio with the absence of clubbing and honeycomb appearance in HRCT increase the likelihood of the illness being NSIP. The usefulness of ATS clinical diagnostic criteria for UIP may be low in Korea.

• Tuberculosis and Respiratory Diseases
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• v.45 no.6
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• pp.1236-1251
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• 1998

Background : TNF-$\alpha$ appears to be a central mediator of the host response to sepsis. While TNF-$\alpha$ is mainly considered a proinflammatory cytokine, it can also act as a direct cytotoxic cytokine. However, there are not so many studies about the relationship bet ween TNF-$\alpha$ level and lung injury severity in ALI, particularly regarding the case of ALI caused by direct lung injury such as diffuse pulmonary infection. Recently, a natural defense mechanism, known as the stress response or the heat shock response, has been reported in cellular or tissue injury reaction. There are a number of reports examining the protective role of pre-induced heat stress proteins on subsequent LPS-induced TNF-$\alpha$ release from monocyte or macrophage and also on subsequent LPS-induced ALI in animals. However it is not well established whether the stress protein synthesis such as HSP can be induced from rat alveolar macrophages by in vitro or in vivo LPS stimulation. Methods : We measured the level of TNF-$\alpha$, the percentage of inflammatory cells in bronchoalveolar lavage fluid, protein synthesis in alveolar macrophages isolated from rats at 1, 2, 3, 4, 6, 12, and 24 hours after intratracheal LPS instillation. We performed histologic examination and also obtained histologic lung injury index score in lungs from other rats at 1, 2, 3, 4, 6, 12, 24 h after intratracheal LPS instillation. Isolated non-stimulated macrophages were incubated for 2 h with different concentration of LPS (0, 1, 10, 100 ng/ml, 1, or 10 ${\mu}g/ml$). Other non-stimulated macrophages were exposed at $43^{\circ}C$ for 15 min, then returned to at $37^{\circ}C$ in 5% CO2-95% for 1 hour, and then incubated for 2 h with LPS (0, 1, 10, 100ng/ml, 1, or 10 ${\mu}g/ml$). Results : TNF-$\alpha$ levels began to increase significantly at 1 h, reached a peak at 3 h (P<0.0001), began to decrease at 6 h, and returned to control level at 12 h after LPS instillation. The percentage of inflammatory cells (neutrophils and alveolar macrophages) began to change significantly at 2 h, reached a peak at 6 h, began to recover but still showed significant change at 12 h, and showed insignificant change at 24 h after LPS instillation compared with the normal control. After LPS instillation, the score of histologic lung injury index reached a maximum value at 6 h and remained steady for 24 hours. 35 kDa protein band was newly synthesized in alveolar macrophage from 1 hour on for 24 hours after LPS instillation. Inducible heat stress protein 72 was not found in any alveolar macrophages obtained from rats after LPS instillation. TNF-$\alpha$ levels in supernatants of LPS-stimulated macro phages were significantly higher than those of non-stimulated macrophages(p<0.05). Following LPS stimulation, TNF-$\alpha$ levels in supernatants were significantly lower after heat treatment than in those without heat treatment (p<0.05). The inducible heat stress protein 72 was not found at any concentrations of LPS stimulation. Whereas the 35 kDa protein band was exclusively found at dose of LPS of 10 ${\mu}g/ml$. Conclusion : TNF-$\alpha$ has a direct or indirect close relationship with lung injury severity in acute lung injury or acute respiratory distress syndrome. In vivo and in vitro LPS stimulation dose not induce heat stress protein 72 in alveolar macrophages. It is likely that 35 kDa protein, synthesized by alveolar macrophage after LPS instillation, does not have a defense role in acute lung injury.