Balb/C mouse의 폐장대식세포에서 유리규산 자극에 의한 Proinflammatory Cytokine과 Cytokine과 TGF-β의 생성 및 상관관계

기신영 ( Shin Young Ki ),김은영 ( Eun Young Kim ),김미호 ( Mi Ho Kim ),어수택 ( Soo Taek Uh ),김용훈 ( Yong Hoon Kim ),박춘식 ( Choon Sik Park ),이희발 ( Hi Bal Lee ) 대한결핵 및 호흡기학회 1998 Tuberculosis and Respiratory Diseases Vol.45 No.4

호산구의 자연사 유도과정에서 cAMP 의존성 경로의 역할

기신영(Shin Young Ki),전기원(Ki Weon Jeon),이명란(Myung Ran Lee),어수택(Soo Taek Uh),김용훈(Yong Hoon Kim),박춘식(Coon Sik Park),정일엽(II Yep Chung) 대한천식알레르기학회 1999 천식 및 알레르기 Vol.19 No.5

Background: Interleukin-5 (IL-5), IL-3, and GM-CSF are known to prolong the survival of eosinophils, and IL-5 has the most potent effect on eosinophil survivaL It is also known that di- vergent signals induce apoptosis in different cells. But, There have been few reports on about the intracellular signals that trigger the effectors of apoptosis. Cyclic AMP (cAMP) can modu- late apoptosis in many cells. But, the role of intracellular cAMP in the IL-5 induced eosinophil survival is still not completely understood. Objectives : This study was aimed to elucidate the role of intracellular cAMP in IL-5 induced eosinophil survival. Material and method: Eosinophils were isolated from peripheral blood of atopic patients. Eosin- ophil viability was measured by means of propidium iodine (PI) method and the number of via- ble cells was counted by FAC scan (Becton Dickinson, USA). Cells were cultured with or with- out IL-5, and also with various cAMP-elevating agents (dibutyryl cAMP, 8-bromo-cAMP, N6- benzoyl cAMP). The concentrations of cAMP were measured by cAMP enzyme immunoassay system(BiotrakTM, Amersham). Finally cAMP dependent protein kinase A inhibitor (H8) was added to eosinophils to examine the effect of decreased intracellular cAMP activity on the via- bility of eosinophils stimulated with IL-5. Results. The percentage of viable eosinophils was reduced rapidly from 92.1±1.8% to 8.23± 3.41% without IL-5 (p<0.05; n=ll, 4-day incubation). Upon addition of IL-5, it was in- creased to 33.02+7.8% (p<0.05; n=ll). In the absence of IL-5, the addition of cAMP-elevat- ing agent increased eosinophil viability in a dose-dependent manner. Upon addition of H8 (24 uM), the eosinophil viability increased by IL-5 (52.5±6.4%) was significantly reduced to 27.2±5.4% (p<0.05;n=7). Compared with tissue culture media (TCM) only, IL-5 produced persis- tent elevation of intracellular cAMP of eosinophils in a time and dose dependent manner.

Phenylpropanolamine 복용후 발생한 뇌경색증 1 예

기신영(Shin Young Ki),최영수(Young Soo Choi),유병우(Byung Woo Yoo),정성환(Seong Whan Jeong),김홍수(Hong Soo Kim),진병원(Byung Won Jin) 대한내과학회 1995 대한내과학회지 Vol.49 No.1

Phenylpropanolamine, a sympathomimetic amine structrally related to ephedrine and amphetamine, is commonly used as a anorectic agent and nasal decongestant. It releases noradrenaline from sympathetic nerve endings and gives a direct stimulation of alpha-adrenoreceptors in blood-vessels. It causes severe hypertension, cerebral hemorrhage, psychosis and central nervous system stimulntion. But the cases of cerebral infarction are very rare and not well known of it's mechanism. But several studies and clinical review suggest that phenylpropanolamine causes vascular spasm and fibrinoid necrosis result in tissue ischemia. We experienced a case of cerebral infarction in a healthy 18-year old woman who had taken 8 tablets of anorectic pill containing phenylpropanolamine 75mg and caffeine 200mg. She had no history of hypertension or drug abuse. She presented stuporous mental status, convulsion and right sided hemiparesis. And we found cerebral infarction in pons and left occipital lobe on brain MRI

노인 천식 환자에서 천식 증상 발현 빈도 및 임상적 특징

김기업(Ki Up Kim),주재학(Jae Hak Joo),김재한(Jae Han Kim),기신영(Shin Young Ki),어수택(Soo Taek Uh),김용훈(Young Hoon Kim),박춘식(Choon Sik Park) 대한천식알레르기학회 2000 천식 및 알레르기 Vol.20 No.1

Background: The clinical and physiological aspects of asthma in the elderly are different from children and young adults. Symptoms such as wheezing, coughing, dyspnea are less commonly reported in the elderly compared to younger patients. Objective : 1) To evaluate the difference of symptoms and physiologic aspects between elderly and younger asthmatics. 2) To determine whether the difference of symptoms is related to changes in physiologic parameters or other clinical features. Subject and method: Sixty-four young, fifty-three-middle aged, and twenty-five elderly stable asthmatic subjects were studied. We conducted questionnaire survey and performed pulmonary function test, allergy skin test and methacholine challenge test. Result : Duration of disease was not different in the three groups. Allergy skin test reactivity rate decreased by age. In the elderly patients, the prevalence of symptoms was significantly lower than in younger patients. There was no correlation between the presence of symptoms, sex, smoking history and alteration of pulmonary function. Conclusion : Compared with younger patients, the symptoms such as coughing, wheezing, and dyspnea are obscure in elderly patients. But the appearance of symptoms is not related to the alteration of physiologic functions. This study emphasizes the importance of routinely performing lung function test in elderly patients to diagnose bronchial asthma, even if their symptoms are not typical.

Balb/C mouse의 폐장대식세포에서 유리규산 자극에 의한 Proinflammatory Cytokine과 TGF-$\beta$의 생성 및 상관관계

기신영,김은영,김미호,어수택,김용훈,박춘식,이희발,Ki, Shin-Young,Kim, Eun-Young,Kim, Mi-Ho,Uh, Soo-Taek,Kim, Yong-Hoon,Park, Choon-Sik,Lee, Hi-Bal 대한결핵및호흡기학회 1998 Tuberculosis and Respiratory Diseases Vol.45 No.4

연구배경: 유리규산(silica) 자극에 의해 폐장내 대식세포에서 형성되는 proinflammatory cytokines인 IL-1$\beta$, IL-6, TNF-$\alpha$와 fibrogenic cytokine인 TGF-$\beta$, PDGF는 섬유화 과정에 매우 중요한 역할을 한다. 그러나 이러한 cytokine 의 역할과 상호관련성에 대해서는 아직 확실히 밝혀진 바없다. 본 연구는 Balb/C mouse의 폐장단구세포를 silica로 자극시 형성되는 IL-6, TNF-$\alpha$ 폐섬유화의 발생과 유지에 중요한 역할을 할 것으로 기대되는 TGF-$\beta$ 의 생성을 관찰하고 TGF-$\beta$의 생성에 proinflammatory cytokine이 미치는 영향에 대해서 알아보고자 하였다. 방 법: Balb/C 의 폐장대식세포를 silica로 자극한 후 IL-6, TNF-$\alpha$ TGF-$\beta$의 양을 bioassay로 측정하였고 mRNA의 발현을 in situ hybridization을 통해 관찰하였으며, 대식세포의 TGF-$\beta$ 생성에 대한 IL-1$\beta$, IL-6, TNF-$\alpha$의 영향을 알기 위하여 L-1, IL-6, TNF-$\alpha$에 대한 중화항체를 이용하여 대식세포의 TGF-$\beta$의 생성 억제 유, 무를 관찰하였다. 결 과: Silica로 대식세포자극시 TNF-$\alpha$는 초기 4 시간째 최고의 생성능을 보였으며, IL-6 는 silica 0.2 ${\mu}g/ml$의 농도에서 배양 8 시간째 생성능이 가장 높았고 배양 12 시간째는 다시 감소하였다가 24시간째 증가하는 biphasic한 소견을 보여 주었다. TGF-$\beta$는 silica의 양과 관계없이 배양 24시간째 자연생성능뿐 아니라, silica로 자극시에도 증가되었다. Silica와 TNF-$\alpha$ 50ng/ml을 함께 자극시 TGF-$\beta$의 생성은 현저히 증가되었으며, TNF-$\alpha$ 50 ng/ml과 IL-6 50 ng/ml으로 동시 자극시에는 TNF-$\alpha$에 의한 TGF-$\beta$의 형성이 증가하는 경향을 보였다. TNF-$\alpha$의 중화항체를 전처치 후 silica 자극시 TGF-$\beta$의 생성능을 억제시킴을 관찰할 수 있었다. Anti-IL-$\beta$, anti-IL-6, anti-TNF-$\alpha$ antibody 모두를 통시에 투여하였을 때도 silica에 의한 TGF-$\beta$의 생성능을 억제시킴을 관찰할 수 있었다. Silica 자극 후 대식세포의 in situ hybridization에서 TNF-$\alpha$ mRNA는 2시간째부터 발현되었고 IL-6 mRNA는 4 시간째부터 발현된 후 8 시간째 소실되었고 TGF-mRNA는 12 시간째 가장 강한 발현을 보였다. 결 론: Silica 자극에 의해 폐장대식세포는 자극 초기에는 TNF-$\alpha$가 가장먼저 형성되고 후기에 TGF-$\beta$가 형성되며 TNF-$\alpha$가 TGF-$\beta$ 형성에 중요한 역할을 할 것으로 사료되었다. Background: Chronic inhalation of silica induces the lung fiborsis. The alveolar macrophages ingest the inhaled silica; they liberate the pro-inflammatory cytokines such as IL-1$\beta$, IL-6, TNF-$\alpha$ and fibrogenic cytokines, TGF-$\beta$ and PDGF. Cytokines liberated from macrophage have pivotal role in pulmonary fibrosis. There is a complex cytokine network toward fibrosis. However, the exact roles and the interaction among the proinflammatory cytokines and TGF-$\beta$, a fibrogenic cytokine, have not been defined, yet. In this study, we investigated silica induced IL-1$\beta$, IL-6, TNF-$\alpha$ and TGF-$\beta$ production and the effect of IL-1$\beta$, IL-6, TNF-$\alpha$ on the production of TGF-$\beta$ from lung macrophages of Balb/C mice. Method: We extracted the lung of Balb/C mice and purified monocytes by Percoll gradient method. Macrphages were stimulated by silica ($SiO_2$) in the various concentration for 2, 4, 8, 12, and 24 hours. The supernatants were used for the measurement of protein levels by bioassay, and cells for the levels of mRNA by in situ hybridization. Results: The production of IL-6 was not observed till 4 hours, and reached the peak levels at 8 hours after stimulation of silica. The production of TNF-$\alpha$ increased from 2 hours and reached the peak levels at 4 hours after stimulation of silica. The spontaneous TGF-$\beta$ production reached the peak levels at 24 hours. TNF-$\alpha$ upregulated the silica induced TGF-$\beta$ production. Silica induced TGF-$\beta$ production was blocked by pretreated anti-TNF-$\alpha$ antibody. In situ hybridization revealed the increased positive signals at 4 hours in IL-6, at 4 hours TNF-$\alpha$ and 12 hours in TGF-$\beta$. Conclusion: The results above suggest that silica induced the sequential production of IL-6, 1NF-$\alpha$ and TGF-$\beta$ from macrophages and TNF-$\alpha$ upregultaes the production of TGF-$\beta$ from silica-induced macrophages.

유리규산에 의한 폐장내 IL-1$\beta$, IL-6, TNF-$\alpha$, TGF-$\beta$의 발현

기신영,박성우,이명란,김은영,어수택,김용훈,박춘식,이희발,Ki, Shin-Young,Park, Sung-Woo,Lee, Myung-Ran,Kim, Eun-Young,Uh, Soo-Taek,Kim, Yong-Hoon,Park, Choon-Sik,Lee, Hi-Bal 대한결핵및호흡기학회 1998 Tuberculosis and Respiratory Diseases Vol.45 No.4

연구배경: 유리규산(silica)이 폐장내로 흡입되면 폐장내 염증세포의 축적이 발생하고 폐실질과 간질에 섬유화가 발생한다. Silica가 폐장내로 흡입되면 대삭세포에 탐식되어 염증매개물을 분비한다. 대식세포에서 염증반응에 중요하게 관여히는 cytokines은 IL-1$\beta$, IL-6, TNF-$\alpha$ 등이 있으며 후기 섬유화에 관계하는 TGF-$\beta$ 등이 분비되어 폐섬유화의 진행과 유지에 중요한 역할을 한다. 그러나 silica에 의한 폐섬유화 과정에서 각 cytokine의 역할과 분비부위 시간에 따른 변화에 대해서는 아직 확실히 규명된 바 없다. 방 법: silica 투여시 폐섬유화증이 잘 유발되어지는 C57BL/6J(ref) mouse의 폐장내로 silica를 투여 후 1 일, 2 일, 7 일, 2 주, 4주, 8주, 12주째마다 폐장을 적출하여 시간에 따른 폐조직의 변화와 면역화학조직염색법을 이용하여 IL-1$\beta$, IL-6, TNF-$\alpha$, TGF-$\beta$ 단백 발현의 변화와 분비부위를 관찰하였다. 결 과: Silica군에서는 2주부터 육안적 소견의 변화가 관찰되었으며 8주째 변화가 가장 심하였고 초기에 염증세포의 침윤이 기관지와 세기관지 주위로 시작되어 8 주째는 기관지 주위의 심한 염증세포 침윤과 섬유화 결절에 의해서 기관지가 완전히 폐쇄되는 소견을 보였다. IL-6 의 발현은 혈관에서는 변화없이 지속적으로 발현되었고 시간 경과에 따라 기도상피세포와 혈판내피세포에서 IL-6 발현이 관찰되어 IL-6의 형성은 혈관에서 기도내로 이동하는 염증세포에 의해 과형성됨을 알 수 있었다. IL-1는 정상군의 혈관내피세포에서 1도 정도의 경한 발현이 있은 후 큰 변화없이 12주까지 지속적으로 발현되었다. TNF-$\alpha$는 기도상피세포에서 발현이 점차 증가하였고 2주째 기관지 주위에 염증세포의 침윤이 심해지면서 형성된 결절에서 강한 발현이 나타난 후 8주까지 지속되었다. TGF-$\beta$는 기관지 주위에서 초기에 발현을 관찰할 수 없었으나 염증 세포의 침윤이 심해지는 2 주째부터 강한 발현이 나타난 후 12주까지 지속적으로 높은 발현을 나타내었다. 결 론: Silica를 폐장내 투여시 IL-1$\beta$, IL-6, TNF-$\alpha$가 조기에 분비되어 모두 폐섬유화의 염증반응에 관여하고 TGF-$\beta$는 후기의 폐섬유화에 유지에 관여할 것으로 추정되며 silica에 의한 폐섬유화의 조절방법으로는 TNF-$\alpha$의 형성조절이 좋은 방법이 될 수 있을 것으로 사료된다. Background: Silica-induced lung diseases is characterized by the accumulation of inflammatory cells at early stage and fibrosis in pulmonary parenchyma and interstitium at late stage. As a consequence of inflammation, silicosis is accompanied with the expansion of interstitial collagen and the formation of fibrotic nodule. In this process, several kinds of lung cells produce cytokines which can amplify and modulate pulmonary fibrosis. The alveolar macrophage is a potent source of proflammatory cytokines and growth factor. But in the process of silicotic inflammation and fibrosis, there are many changes of the kinetics in cytokine network. And the sources of cytokines in each phase are not well known. Method: 2.5 mg of silica was instillated into the lung of C57BL/6J mice. After intratracheal instillation of silica, the lungs were removed for imunohistochemical stain at 1, 2, 7 day, 2, 4, 8, 12 week, respectively. We investigated the expression of IL-1$\beta$, IL-6, TNF-$\alpha$ and TGF-$\beta$ in lung tissue. Results: 1) The expression of IL-6 increased from 1 day after exposure to 8 weeks in vascular endothelium. Also peribronchial area were stained for IL-6 from 7 days and reached the peak level for 4 weeks. 2) The IL-1 $\beta$ was expressed weakly at the alveolar and peribronchial area through 12 weeks. 3) The TNF-$\alpha$ expressed strongly at alveolar and bronchial epithelia during early stage and maintained for 12 weeks. 4) TGF-$\beta$ was expressed strongly at bronchial epithelia and peribronchial area after 1 week and the strongest at 8 weeks. Conclusion: The results above suggests IL-6, TNF-$\alpha$ appear to be a early inflammatory response in silica induced lung fibrosis and TGF-$\beta$ play a major role in the maintenance and modulation of fibrosis in lung tissue. And the regulation of TNF-$\alpha$ production will be a key role in modultion of silica-induced fibrosis.

파슬리 의존성 운동 유발성 아나필락시스 1례

전기원(Ki Won Jeon),김철(Chul Kim),김양기(Yang Ki Kim),강문수(Moon Soo Kang),봉종대(Jong Dae Bong),기신영(Shin Young Ki),어수택(Soo Taek Uh),김용훈(Yong Hoon Kim),박춘식(Choon Sik Park) 대한천식알레르기학회 1998 천식 및 알레르기 Vol.18 No.4

Exercise-induced anaphylaxis can be associated with ingestion of a specific food. We ex- perienced a case of exercise-induced anaphylaxis followed by ingestion of parsely. A 22- year old female patient was presented with angioedema of the face and chest tightness in- duced by running after ingestion of parsley within 15 minutes. She had suffered from allergic rhinitis. She had positive reactions to mugwort pollen and parsely extract on skin prick test in a dose dependent manner. Although the oral provocation test with parsely could not induce bronchoconstriction, we could diagnosed as parsely dependent exercise induced anaphylaxis based upon skin prick test and history.

아스페르길루스와 연관된 기관지중심성 육아종증

김양기 ( Yang Ki Kim ),전기원 ( Ki Won Jun ),김철 ( Chul Kim ),김기업 ( Ki Up Kim ),기신영 ( Shin Young Ki ),어수택 ( Soo Taek Uh ),김용훈 ( Yong Hoon Kim ),박춘식 ( Chun Sik Park ) 대한결핵 및 호흡기학회 1998 Tuberculosis and Respiratory Diseases Vol.45 No.6

기침형 천식에서 항염증 흡입제 치료 경과에 따른 기도과민성 변화에 대한 고찰

문승혁 ( Seung Hyug Moon ),기신영 ( Shin Young Ki ),김용훈 ( Yong Hoon Kim ),박춘식 ( Choon Sik Park ) 대한결핵 및 호흡기학회 1998 Tuberculosis and Respiratory Diseases Vol.45 No.5

섬유모세포에서 내독소 자극에 따른 Interleukin - 6 생성의 신호전달과정

주재학(Jae Hak Joo),기신영(Shin Young Ki),문승혁(Seung Hyek Moon),정성환(Seong Hwan Jung),김현태(Hyeon Tae Kim),어수택(Soo Taek Uh),김용훈(Yong Hoon Kim),박춘식(Choon Sik Park) 대한내과학회 1998 대한내과학회지 Vol.54 No.3

Objectives: Stimulation of cell results in a variety of early biochemical events, known as signal transduction pathway and ultimately leads to final outcome like cell proliferation or cytokine production. The intracellular signal transduction pathway of IL-6 production by LPS stimulated fibroblast is not well defined. In present study, we investigated what signal transduction pathway is involved in IL-6 production. Methods: We examined the effects of various inhibitors of signal transduction pathway including pertussis toxin, cholera toxin, genistein, indomethacin, EDTA, nifedpine, sphingosine, staurosporine, and HH on the production of IL-6 by human fetal fibroblast MRC-5 after stimulation with LPS. IL-6 was measured by bioassay in supernatant of LPS stimulated fibroblast MRC-5 after pretreatment with inhibitors. Results: Calcium inhibitor (EDTA) and protein kinase inhibitor (staurosporine) reduced IL-6 production by LPS stimulated fibroblast. Protein tyrosine kinase inhibitor((Genistein) and PKC inhibitor(sphingosine) had no influence on IL-6 production. Cholera toxin and prostaglandin inhibitor (indomethacin) led to increase in IL-6 production by LPS stimulated fibroblasts. Conclusion: These results suggest that G protein associated receptors, through the calcium dependent pathway, are working in IL-6 production by LPS stimulated fibroblasts.