간섬유화(경화)를 유도한 실험동물에서 생약 추출물(LH)의 항산화와 항섬유화 효과 검색 The Screening of Antioxidant and Antifibrotic Effect from Water Extracts of Herbs(LH) in Biliary Liver Fibrosis (Cirrhosis) Induced Rsts원문보기
The pathogenesis of cholestatic liver injury as well as the modulation of hepatic fibrogenesis is causally associated with involvement of reactive oxygen species (ROS) and free radical reactions. In this study, we investigated whether dried extracts of oriental medicine (LH) have antioxidant and ant...
The pathogenesis of cholestatic liver injury as well as the modulation of hepatic fibrogenesis is causally associated with involvement of reactive oxygen species (ROS) and free radical reactions. In this study, we investigated whether dried extracts of oriental medicine (LH) have antioxidant and antifibrotic effect under the biliary liver fibrosis (cirrhosis) c ondition. The female Sprague-Dawley rats were divided in six groups (Normal, N-LH, op-2, op-4, opLH-2, opLH-4) and were observed in 2 weeks or 4 weeks. For this purpose the rats were operated by bile duct ligation/scission (BDL/S), which induced to liver fibrosis and cirrhosis. After surgery, the prepared LH was administered p.o. 2 mι/day/rat in 2 weeks or 4 weeks for opLH groups. During the observation period, jaundices appeared in eyes, ears and tail of all BDL/S operated rats. And at the time of sacrifice, cholestasis was observed in proximal bile duct, especially the color of bile juice and urine in opLH-4 group showed more clear than op-2, op-4 and opLH-2 group. The value of clinical parameters and product of lipid peroxidation (MDA) in sera and the hydroxyproline (hyp) content in liver tissue were significantly increased in all liver fibrosis (cirrhosis) developed rats (p＜0.001~0.05). Among the clinical parameters of sera, value of BUN, ALP in opLH-4 group showed significantly lower than in op-4 group (p＜0.05, p＜0.001). The content of hyp in opLH-2, opLH-4 group (478.0 $\pm$ 134.3 $\mu\textrm{g}$/g 897.5 $\pm$ 118.2 $\mu\textrm{g}$/g) showed lower than in op-2, op-4 group (528.9 $\pm$ 220.7 $\mu\textrm{g}$/g, 1023.8 $\pm$ 277.1 $\mu\textrm{g}$/g) and then the value of MDA in opLH-4 was also significantly reduced to 59.4% of that in op-4 group (p＜0.001). The histological change (bile duct proliferation, fibrosis, collagen bundle) was similarly observed in op-2 group and in opLH-2 group, but the weak fibrosis and bile duct proliferation were observed in opLH-4 group compared with in op-4 group. Our data indicate that the 4 weeks treatment with LH extract suppressed lipid peroxidation and inhibited fibrotic (cirrhosis) process, and experimental cholestatic liver disease is associated with increased lipid peroxidation in BDL/S operated rats. Hence we concluded that the measurement of MDA and hyp can be useful monitor for the screening of antioxidant and antifibrotic effect in experimental liver fibrosis (cirrhosis), and LH has been shown to have hepatoprotective effect, antifibrotic effect and antioxidant effect.
The pathogenesis of cholestatic liver injury as well as the modulation of hepatic fibrogenesis is causally associated with involvement of reactive oxygen species (ROS) and free radical reactions. In this study, we investigated whether dried extracts of oriental medicine (LH) have antioxidant and antifibrotic effect under the biliary liver fibrosis (cirrhosis) c ondition. The female Sprague-Dawley rats were divided in six groups (Normal, N-LH, op-2, op-4, opLH-2, opLH-4) and were observed in 2 weeks or 4 weeks. For this purpose the rats were operated by bile duct ligation/scission (BDL/S), which induced to liver fibrosis and cirrhosis. After surgery, the prepared LH was administered p.o. 2 mι/day/rat in 2 weeks or 4 weeks for opLH groups. During the observation period, jaundices appeared in eyes, ears and tail of all BDL/S operated rats. And at the time of sacrifice, cholestasis was observed in proximal bile duct, especially the color of bile juice and urine in opLH-4 group showed more clear than op-2, op-4 and opLH-2 group. The value of clinical parameters and product of lipid peroxidation (MDA) in sera and the hydroxyproline (hyp) content in liver tissue were significantly increased in all liver fibrosis (cirrhosis) developed rats (p＜0.001~0.05). Among the clinical parameters of sera, value of BUN, ALP in opLH-4 group showed significantly lower than in op-4 group (p＜0.05, p＜0.001). The content of hyp in opLH-2, opLH-4 group (478.0 $\pm$ 134.3 $\mu\textrm{g}$/g 897.5 $\pm$ 118.2 $\mu\textrm{g}$/g) showed lower than in op-2, op-4 group (528.9 $\pm$ 220.7 $\mu\textrm{g}$/g, 1023.8 $\pm$ 277.1 $\mu\textrm{g}$/g) and then the value of MDA in opLH-4 was also significantly reduced to 59.4% of that in op-4 group (p＜0.001). The histological change (bile duct proliferation, fibrosis, collagen bundle) was similarly observed in op-2 group and in opLH-2 group, but the weak fibrosis and bile duct proliferation were observed in opLH-4 group compared with in op-4 group. Our data indicate that the 4 weeks treatment with LH extract suppressed lipid peroxidation and inhibited fibrotic (cirrhosis) process, and experimental cholestatic liver disease is associated with increased lipid peroxidation in BDL/S operated rats. Hence we concluded that the measurement of MDA and hyp can be useful monitor for the screening of antioxidant and antifibrotic effect in experimental liver fibrosis (cirrhosis), and LH has been shown to have hepatoprotective effect, antifibrotic effect and antioxidant effect.
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문제 정의
이에 본 연구에서는 복합생약 추출물(LH)의 항섬유화 효과와항산화 효과를 검색하기 위해 혈청 생화학적 검사, 간조직중 hyp (총 sllagen)양과 지질과산화물인 MDA 농도를 측정하여 효과를 검 색하였다. 그 결과, 정상군을 제외한 나머지군, 즉 간섬유화(경 화)를 유도한 수술군(op-2, op-4)과 LH를 투여 한 수술군 (opLH-2, opLH-4) 모두에서 눈, 귀, 꼬리에서 황달이 출현하였고 담도결찰부위 (proximal bile duct)에서 담즙울체가 관찰되었다.
이에 본 연구에서는 항산화효과가 있는 약물(천연물)을 대상으로 항산화와 항섬유화 효과를 알아보기 위하여 간섬유화를 유도한 랫드에 복합생약 추출물을 2주, 4주간 투여하여 간기능의지표인 생화학적 수치 및 결합조직 단백의 변화를 나타내는 coBagen 양(hyp)과 지질 과산화정도를 나타내는 MDA를 측정 및관찰하였다.
가설 설정
Fig. 2 - The diagrams of (a) hyp in liver tissue and (b) MDA in sera of rats. significantly different from normal (p<0.
제안 방법
Alanine transaminase(ALT), Aspartate transaminase(AST), Alkaline phosphatase(ALP), total bilirubin, BUN, creatinine 을 MBL-kit를 사용하여 분석하였다.
동물을 2주, 4주간의 관찰 후, 부검시 심장에서 채혈하여 실온에서 3시간 이상 방치한 다음 3000 rpm에서 10분간 원심분리하여 얻은 혈청은 생화학적 검사에 사용하였고, 간의 일부는 hydroxyproline 측정을 위하여 -70℃에서 보관하였으며 나머지 간 조직은 10% 중성 포르말린에 고정하여 hematoxylin & eosin, Masson's trichrome 염색에 사용하였다.
정상군을 제외한 군의 흰쥐에 Kountras 등3分의 방법에 따라담도결찰(proximal, distal bile duct ligation/scission)을 하여 간 섬유화를 유도하였다. 한국 생약협회에서 구입한 LH[결명자(3 g), 차전자(3 g), 지구자(10 g)]는 물(500 m/)과 혼합하여 전제(煎 劑)한 후 여과하였으며 2주와 4주간 경구투여 (2 m//day/rat)하였다.
대상 데이터
10주령 Sprague-Dawley 흰쥐를 6개 군(정상군, 정상 LH군, op-2군, op4군, opLH-2구 opLH4군)也로 구분하여 사육하였다. 사육환경은 밤과 낮의 리듬을 구분하였고 사료와 물은 자유롭게공급하였다.
Student's t-test를 사용하여 mean 土 SD으로 표시하였고 p- value를 구하여 유의성을 검증하였으며 각 parameter들 사이의상관긔계 (regression)를 조사하였다.
이론/모형
간조직내 hydrox刈proline(hyp)양의 측정은 Jamall 등葵의 방법에 따라 간조직을 염산으로 가수분해시켜 isopropylalcohol을 넣고 chloramine-T로 산화시 킨 후, Ehrlich's reagent solution(p- dimethylaminobenzaldehyde)으로 발색시켜 558 nm에서 흡광도를 측정하여 계산하였다.
간조직을 H&E, Masson's trichrome 방법으로 염색한 후, 광학현미경으로 관찰하였다. 조직소견은 담관증식, 섬유화, 염증, scar formation의 정도를 +, ++, + + +로 표시하였다.
성능/효과
005, Table I). Op 군과 opLH군을 비교했을 때 신장과 비장의 무게는 op-2군보다 opLH・2군에서 낮게 나타났으나, 간무게와 간/체중비는 opLH-2 군에서 op-2군보다 높게 나타났고, opLH-4군에서는 간, 신장, 비장의 무게와 장기/체중비 모두 op・4군보다 낮거나 비슷하였다 (Table I).
I). 간무게는 정상군보다 op-2, op-4, opLH-2, op LH~4군에서 모두 유의성 있게 높게 나타났고(pv0.005~0.05), 또한 간 /체중비는 op-4군, opLH-4군 뿐만 아니라 op-2, opLH-2군에서도 정상군보다 유의성 있게 높게 관찰되었다(pv0.005, Table I). Op 군과 opLH군을 비교했을 때 신장과 비장의 무게는 op-2군보다 opLH・2군에서 낮게 나타났으나, 간무게와 간/체중비는 opLH-2 군에서 op-2군보다 높게 나타났고, opLH-4군에서는 간, 신장, 비장의 무게와 장기/체중비 모두 op・4군보다 낮거나 비슷하였다 (Table I).
간섬유화 지표인 hyp양은 정상군보다 수술군(op-2, op-4, opLH-2, opLH-4)에서 3.7~8.2배 유의성 있게 높게 관찰되었다 (p<0.001~0.05). 그러나 op군과 opLH군을 비교하면 opLH-2, opLH-4군(478.
검 색하였다. 그 결과, 정상군을 제외한 나머지군, 즉 간섬유화(경 화)를 유도한 수술군(op-2, op-4)과 LH를 투여 한 수술군 (opLH-2, opLH-4) 모두에서 눈, 귀, 꼬리에서 황달이 출현하였고 담도결찰부위 (proximal bile duct)에서 담즙울체가 관찰되었다. 틀히 opLH-4군의 담즙과 소변의 색이 op-2, op-4군과 opLH- 2군보다 맑고 투명하였다.
그리고 opLH-4군을 opLH-2군과 비교했을 때, BUN과 ALR MDA의 수치는 LH투여 2주에는 증가하는 양상을 보였으나 4주후에는 각각 19.1%, 37.6%, 59.4%로 유의성있게 감소했으며 (p<0.05~0.001), AST(16.6%<21.7%)와 hyp(9.6%<12.3%)는 LH투여 2주보다는 4주후에 많은 감소율을 나타냈다(Fig. 1, 2). 또한 비투여군(op-4)과 비교했을 때 복합생약 추출액 LH의 4주투여군(opLH-4)에서 AST, ALT hypS] 낮은 수치와 유의성 있게낮은 ALE BUN 그리고 MDA 수치가 나타남으로써 적어도 4주간 투여시 뚜렷하게 항산화, 항섬유화 효능이 있다고 생각된다.
특히 op-4군에서는 두꺼운 collagen bundle, portal- portal septum 과 scar formation0] 관찰되었다. 그리고 opLH・4군에서 간세포의 종창은 op-4군보다 약하게 나타났고, 세포질의 파괴와 핵붕괴도 op-4군보다는 상태가양호한 것으로 관찰되었다(Fig. 3, Fig. 4).
1, 2). 또한 비투여군(op-4)과 비교했을 때 복합생약 추출액 LH의 4주투여군(opLH-4)에서 AST, ALT hypS] 낮은 수치와 유의성 있게낮은 ALE BUN 그리고 MDA 수치가 나타남으로써 적어도 4주간 투여시 뚜렷하게 항산화, 항섬유화 효능이 있다고 생각된다.
본 연구결과로써 혈청 중 MDA의 측정과 간조직중 hyp 측정은 항산화와 항섬유화 효과의 동시검색에 사용할 수 있는 좋은 지표이며, 복합생약 추출액(LH)을 2주 보다는 4주간 투여하는 것이 바람직하고 LH는 간기능 개선과 항산화 및 항섬유화 효과가 있을 가능성이 높다고 사료된다.
1). 이러한 결과로 LH의 4주간 투여가 간경화에 의한 glomerular nephritis 의발생을 예방하는 것으로 생각된다.
일반적인 관찰 - 간섬유화(경화)를 유도한 op-2, op-4군 그리고 LH1 구투여군인 opLH-2, opLH・4군 모두에서 정상군과 비교했을 띠 〒 와 눈주위에서 황달이 출현하였고, proximal bile duct 에스己 담즙울체가 관찰되었으며, opLH・2, opLH-4군의 담즙색은 op-2, op-4군보다 맑은 것으로 나타났다.
조직학적 변화 - 정상군보다 op-2, op-4군과 opLH-2, opLH-4 군에서 담관증식(+ + ~ + + +), 섬유화(+ + ~ + + +), portal triads에서 과도한 collagen fiber축적 그리고 간세포 팽더와 핵붕괴 등이 관찰되었다. 그러나 opLH-4군에서의 담관증식은 주로 portal triads에 편재되어 있고 stroma에서는 적게 나타났으나, op-4군에서는 portal triads 뿐만 아니라 stroma에서도 담관증식이 관찰되었다(Fig.
체줌, 장기 무게 및 장기阔I중 변화 - 정상군에 비해서 간섬유화를 유도한 op군과 opLH군에서 간종대와 비종대가 나타났다 (Table I). 간무게는 정상군보다 op-2, op-4, opLH-2, op LH~4군에서 모두 유의성 있게 높게 나타났고(pv0.
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