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요독증 환자의 면역 반응 - B 형 간염백신 접종후 anti - HBs 양성반응자와 음성반응자사이의 체외 T 림프구 반응의 차이 -
이희발(Hi Bahl Lee),박춘식(Choon Sik Park),장우현(Woo Hyon Chang) 대한내과학회 1990 대한내과학회지 Vol.39 No.5
N/A Uremia is associated with impaired immune responses and yet the in vitro lymphocyte responses to mitogens in dialysis patients have been variously reported as decreased, normal or even increased. We studied the proliferative responses of peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA), mitogenic monoclonal antibody, anti-CD3, and a mitogenic combination of anti-CD2, monoclonal antibodies, 9-1 and 9.6, mitogen-indnced interleukin 2 (IL-2) production and IL-2 receptor (IL-2R) expression and finally the effect of exogenous IL-2 on the proliferative responses of PBMC to PHA and anti-CD3, in 21 dialysis patients and 12 normal controls. All subjects received three injections of 20㎍ hepatitis B vaccine. All 12 control subjects (NC) and 16 dialysis patients (UR) were responders, and 5 patients were nonresponders (UNR) to hepatitis B vaccine. Proliferative responses to PHA and anti-CD3, were normal in UR but significantly impaired in UNR. Responses to anti-CD2, were normal in both UR and UNR. Mitogen-induced IL- production was exaggerated in UR but normal in UNR. Mitogen-induced IL-2R expression was normal in both UR and UYR. Exogenous IL-2 failed to normalize the proliferative responses of PBMC from UNR to PHA and anti-CD3. In conclusion, uremic responders to hepatitis B vaccine had noraml in vitro cellular immune responses while uremic nonresponders to the vaccine had significantly impaired in vitro proliferative responses despite normal IL-2 production and IL-2R expression. The mechanisms of impaired cellular immune responses in uremic nonresponders were not clear at this time, but evidence suggests that functional defects of monocytes as well as T cells may exist in these patients.
요독증 환자의 면역 반응 - 2. B 형 간염 바이러스 보균자의 체외 T 세포 반응 -
이희발(Hi Bahl Lee),박춘식(Choon Sik Park),조성원(Sung Won Cho),한동철(Dong Cheol Han),황승덕(Seung Duk Hwang) 대한내과학회 1991 대한내과학회지 Vol.40 No.5
N/A Background. The underlying mechanisms that lead to the development of the chronic HBsAg carrier state are not known. Host cellular and humoral immune responses are suspected of being important. Thus the chronic carrier state is particularly common among individuals with conditions or diseases associated with significant immunologic hyporesponsiveness such as uremia, Down s syndrome, leukemia and leprosy. Methods. In vitro T cell proliferative responses to phytohemagglutinin(PHA), mitogenic anti-CD3 monoclonal antibody and mitogenic combination of anti-CD2 9-1 and 9.6 and mitogen-induced interleukin-2(IL-2) and 2'5'-oligoadenylate synthetase (2'5'-AS) production were studied in 7 asymptomatic uremic HBsAg carriers (UC), 11 non-uremic asymptomatic carriers (NC), 6 uremic responders (1JR) and 12 non-uremic responders (NR) to hepatitis B vaccine in order to study immune responses of uremic HBsAg carriers. Peripheral blood mononuclear cells (PBMC) were separated by Ficoll-Hypaque gradient centrifugation. IL-2 production was measured by ELISA method and 2'5'-AS by RIA. Results. 1) The number of circulating lymphocytes was significantly lower in UC than in NR and NC. 2) Proliferative responses of PBMC from UC were not different from those of NR, NC, and UR. 3) IL-2 production was significantly higher in PHA- stimulated than in unstimualted cultures in all 4 groups but was most prominent in UR. Both unstimulated and stimulated IL-2 production were highter in NC, UR, and UC than in NR. 4) 2'5'-AS production was significantly greater in PHA-stimulated than in unstimulated cultures in all 4 groups but was significantly lower in UC than in NR or UR. No difference was observed between NC and UC. Conclusion. It appears that the defect in interferon production may play an important role in the development and maintenance of chronic HBsAg carrier state in uremia.
Precore 유전자의 변이형 B 형 간염 바이러스 감염의 임상적 의의
조성원(Sung Won Cho),이희발(Hi Bahl Lee) 대한내과학회 1994 대한내과학회지 Vol.47 No.6
N/A Objectives: To determine the prevalence and clinical implication of precore mutant, we examined the presence of wild type and precore mutant HBV in sera from a total of 64 patients including 52 patients with chronic liver disease type B and 12 asymptomatic HBsAg carriers by using an oligonucleotide hybridization assay. Methods: The entire precore region was amplified by the polymerase chain reaction and hybiridized with non-mutated, one and two point mutated probes. The speicficity was confirmed by the use of cloned HBV and direct sequencing in some samples. Results: Precore mutant HBV was detected in 30 of 64 subjects. Among 12 of 19 HBeAg negative patients in whom precore mutant HBV was detected, one had an homogenous precore mutant viremia and 11 had a mixed viremia with precore mutant HBV as more prevalent virus. Among 33 HBeAg positive patients with chronic liver disease, 16 had a mixed viremia with precore mutant as less prevalent virus and 17 had an homogenous wild type HBV population. Among 5 HBeAg negative asymptomatic carriers, 2 had an homogenous precore mutant viremia and one had an homogenous wild type viremia. All 7 HBeAg positive asymptomatic carriers had an homogenous wild type HBV population. Precore mutant HBV did not appear or appeared at very low levels after HBeAg seroconversion in patients whose ALT levels remained persistently normal after the seroconversion. In patients who had flare up of ALT after HReAg seroconversion, precore mutant HBV appeared at high levels after the seroconversion. Conclusion: These results suggest that precore mutant HBV infection is common and that the HBeAg/anti-HBe status is determined by the relative prevalence of wild versus mutant viremia in an endemic area for HBV. Active replication of precore mutant HBV may be one of many factors inducing liver cell injury.
사람 폐 섬유아세포의 전환성장인자-β1에 의한 fibronectin 분비와 α-smooth muscle actin 표현에 있어서 활성산소족의 역할
하헌주,유미라,어수택,박춘식,이희발,Ha, Hunjoo,Yu, Mi-Ra,Uh, Soo-taek,Park, Choon Sik,Lee, Hi Bahl 대한결핵및호흡기학회 2005 Tuberculosis and Respiratory Diseases Vol.58 No.3
연구배경 : 전환성장인자-${\beta}1$(transforming growth factor-${\beta}1$: $TGF-{\beta}1$)은 폐 섬유화를 매개하는 주된 인자이지만 $TGF-{\beta}1$에 의한 폐 섬유화의 발생과 진행기전의 이해는 아직 불완전하다. $TGF-{\beta}1$은 다양한 세포에서 활성산소족(reactive oxygen species: ROS)을 통하여 세포내 신호를 전달하고 ${\alpha}$-smooth muscle actin (${\alpha}$-SMA)의 신생합성을 통하여 상피세포와 폐 섬유아세포를 근 섬유아세포 표현형으로의 변화를 유도하는 주된 인자이다. ROS는 또 다양한 세포에서 세포외기질 (extracellular matrix: ECM) 축적을 유발하는 것이 알려져 있음으로 본 연구에서는 폐 섬유아세포인 MRC-5 세포에서 $TGF-{\beta}1$이 ROS를 매개하여 fibronectin 분비와 ${\alpha}-SMA$ 표현의 증가에 관여하는지를 검색하였다. 방 법 : 성장이 동일화된 MRC-5 세포를 $TGF-{\beta}1$ (0.2-10ng/ml)으로 96 시간까지 자극하였고, 필요에 따라 항산화제인 N-acetylcysteine (NAC)이나 NADPH oxidase 억제제인 diphenyleniodonium (DPI)을 $TGF-{\beta}1$ 투여 1 시간 전부터 전처리하였다. Dichlorofluorescein (DCF)에 민감한 세포내 ROS는 FACS로, 분비된 fibronectin과 세포의 ${\alpha}-SMA$ 표현은 Western blot 분석으로 측정하였다. 결 과 : $TGF-{\beta}1$은 용량의존적으로 fibronectin 분비와 ${\alpha}-SMA$ 표현을 상향조절하였다. NAC와 DPI는 $TGF-{\beta}1$에 의한 fibronectin 분비 증가와 ${\alpha}-SMA$ 상향조절을 유의하게 억제하였다. $TGF-{\beta}1$에 의한 세포내 ROS의 증가도 NAC나 DPI에 의하여 유의하게 억제되었다. 결 론 : 본 연구의 결과는 폐 섬유아세포에서 NADPH oxidase 에 의하여 생산된 ROS가 $TGF-{\beta}1$에 의한 fibronectin 분비와 ${\alpha}-SMA$ 표현을 상향조절함으로써 폐 섬유화의 발생과 진행에 관여할 수 있음을 증명하였다. Background : The transforming growth $factor-{\beta}1$ ($TGF-{\beta}1$) plays a key role in lung fibrosis. However, the molecular mechanisms involved in $TGF-{\beta}1$-induced lung fibrosis are unclear. $TGF-{\beta}1$ is the key inducer of myofibroblast transdifferentiation via de novo synthesis of ${\alpha}-smooth$ muscle actin (${\alpha}-SMA$). Since $TGF-{\beta}1$ signals through reactive oxygen species (ROS) and ROS have been shown to induce accumulation of extracellular matrix (ECM) in various tissues, this study examined if ROS play a role in $TGF-{\beta}1$-induced fibronectin secretion and ${\alpha}-SMA$ expression in human lung fibroblasts, MRC-5 cells. Methods : Growth arrested and synchronized MRC-5 cells were stimulated with $TGF-{\beta}1$ (0.2-10 ng/ml) in the presence or absence of N-acetylcysteine (NAC) or diphenyleneiodonium (DPI) for up to 96 hours. Dichlorofluorescein (DCF)-sensitive cellular ROS were measured by FACScan and secreted fibronectin and cellular ${\alpha}-SMA$ by Western blot analysis. Results : $TGF-{\beta}1$ increased the level of fibronectin secretion and ${\alpha}-SMA$ expression in MRC-5 cells in a dosedependent manner. Both NAC (20 and 30 mM) and DPI (1 and $5{\mu}M$) significantly inhibited $TGF-{\beta}1$-induced fibronectin and ${\alpha}-SMA$ upregulation. The $TGF-{\beta}1$-induced cellular ROS level was also significantly reduced by NAC and DPI. Conclusions : The results suggest that NADPH oxidase-dependent ROS play an important role in $TGF-{\beta}1$-induced fibronectin secretion and ${\alpha}-SMA$ expression in MRC-5 cells, which leads to myofibroblast transdifferentiation and progressive lung fibrosis.