Effects of colchicine on renal fibrosis and apoptosis in obstructed kidneys

( Sejoong Kim ),( Eun Sook Jung ),( Jeonghwan Lee ),( Nam Ju Heo ),( Ki Young Na ),( Jin Suk Han ) 대한내과학회 2018 The Korean Journal of Internal Medicine Vol.33 No.3

Background/Aims: Colchicine is an established drug for microtubule stabilization that may reduce tissue injury. No data were available that its effects may depend on the dosage of colchicine. We investigated the anti-fibrotic and apoptotic effects of various dose of colchicine in a unilateral ureteral obstruction (UUO) model. Methods: Thirty-six Sprague-Dawley rats were randomly assigned into six groups. Two sham groups were divided into a vehicle-treated or colchicine-treated group (100 μg/kg/day). Four UUO groups were treated with either vehicle or three different doses of colchicine for 7 days (30, 60, and 100 μg/kg/day, intraperitoneally). All of the animals were sacrificed on day 7. Results: Colchicine treatment diminished acetylated α-tubulin and tumor growth factor-β immunoreactivities in the cortical area of the 7-day obstructed kidneys, which was in dose dependent manner. Colchicine attenuated tubulointerstitial damage and apoptosis in both cortical and medullary area, and beneficial effects of colchicine therapy were dramatically shown at the higher dosage of colchicine. The expression levels of cleaved caspase-3, ED-1, and fibronectin were decreased in UUO animals. Conclusions: We found that the proper dosage of colchicine may have anti-fibrotic and anti-apoptotic effects in obstructed kidneys. For clinical applications, an optimal dose of colchicine should be evaluated to maximize the prevention of renal disease progression.

상백피의 colchicine 유도 비만세포 활성화 억제효과

채옥희(Ok Hee Chai),이종인(Jong In Lee),이무삼(Moo Sam Lee) 대한해부학회 1999 Anatomy & Cell Biology Vol.32 No.5

비만세포의 안정화작용을 가진 상백피가 colchicine에 의하여 유도되어지는 비만세포의 활성화를 억제하는지 알아보고 그 기전이 무엇인지를 파악하기 위하여 비만세포의 형태변화, 히스타민 유리 및 칼슘유입에 대한 실험을 실시하여 다음과 같은 결과를 얻었다. 1. Colchicine은 비만세포의 형태를 원형이나 난원형에서 세포질의 한쪽 또는 양쪽 극이 볼록해지는 표주박모양, 땅콩모양 등으로 변화시켰으며, 이런 비만세포의 핵은 세포의 중심에서 외곽으로 이동되어 있었다. 그러나 상백피를 전처리한 결과 이러한 현상이 70% 이상 억제되었다. 2. Colchicine은 흰쥐 복강 비만세포로부터 히스타민유리와 칼슘유입을 유도하였으나, 정상 대조군과 유의성있는 차이는 없었으며 상백피를 전처리한 결과 히스타민유리와 칼슘유입이 억제되었다. 이상의 결과로 보아 상백피는 비만세포내로의 칼슘유입을 억제함으로써 colchicine에 의한 비만세포의 형태변화와 히스타민 유리를 억제하는 것으로 생각된다. Cortex mori (Morus alba L. : Sangbaikpi), the root barks of mulberry tree, has been used as an antiphlogistic, diuretic, and expectorant in herbs. Previous studies have demonstrated that the phenolic extracts of Cortex mori have hypotensive, hypoglycemic, antifungal, antiviral, antiinflammatory, and anticancer effects, and the hot water extract from Cortex mori has the inhibitory effects on compound 48/80-induced mast cell degranulation and histamine release from rat mast cells (RMCs). Colchicine, an alkaloid found in the crocuslike plant, has been known as an inhibitor of mitosis and microtubule assembly by formation of tubulin-colchicine complex. The purpose of this study was to examine the effect of Cortex mori on the colchicine-induced mast cell degranulation, histamine release, and calcium uptake as a part of the study of the role of microtubules in the mast cell secretory process and the inhibitory mechanism of Cortex mori. The results were summarized as follows. Cortex mori sigif icantly inhibited the colchicine-induced cytomorphological changes of RMCs such as displacement of the nucleus to the periphery, pronounced anisodiametry of the cytoplasm, stubby or broad cytoplasmic mass. Colchicine induced histamine release from RMCs and calcium uptake into RMCs, but it was not signif icantly , compared to those of negative control group. Cortex mori inhibited the colchicine-induced histamine release from RMCs and calcium uptake into RMCs. Above results, it is suggested that Cortex mori has an activity to inhibit the colchicine-induced cytomorphological changes by inhibition of calcium uptake into the mast cells.

Dupuytren 연축에서 콜키신의 치료효과: 예비연구

이영호 ( Young Ho Lee ),최성재 ( Seong Jae Choi ),지종대 ( Jong Dae Ji ),송관규 ( Gwan Gyu Song ) 대한류마티스학회 1998 대한류마티스학회지 Vol.5 No.2

Objective: The treatment of Dupuytren`s contracture has not been entirely satisfactory. We investigated the effectiveness of colchicine, known to inhibit fibroblastic activity, induce collagenase activity and decrease collagen synthesis, in the treatment of Dupuytren`s contracture. Methods: Colchicine was administered orally for 2-12 months to 10 previously untreated patients with Dupuyten`s contracture. We evaluated the effectiveness of the treatment based on subjective(pain) and objective(finger movement, nodule or band size, digital contracture, skin tethering) criteria. Results: 1) Pain and more than one of objective criteria improved in 5 of the 10 patients after colchicine therapy. 2) Dupuytren`s contracture disappeared in 4 of the 10 patients after colchicine therapy. 3) As one patient had no improvement of Dupuytren`s contracture 5 months after colchicine treatment, she was injected with steroid. But she experienced recurrence of the disease 5 months after steroid injection and she was retreated with colchicine. She finally showed the improvement of the disease 2 months after colchicine therapy. 4) Side effect due to colchicine was not found in any of the patients. Conclusion: Although this is a pilot study, colchicine seems to be effective in the treatment of Dupuytren`s contracture. Hereafter a prospective controlled double-blind study is needed to verify this effectiveness of colchicine treatment in Dupuytren`s contracture.

實驗的 肝纖維症에 對한 Colchicine과 Zinc Sulfate의 效果

郭東協,金仁山,曺準承 慶北大學校 醫科大學 1987 慶北醫大誌 Vol.28 No.4

교원질의 합성과 분비를 억제하고 교원질 분해효소의 활성을 증가시키는 작용을 한다고 알려진 colchicine과 교원질의 proline 4-hydroxylation을 방해하여 교원질 형성을 억제한다는 아연의 항섬유화 효과를 알아보기 위하여 실험적으로 간섬유증을 유발시킨 흰쥐에 투여하였다. 간섬유의 유발은 사염화탄소를 반복투여해서 일으켰으며 colchicine과 아연의 효과를 알아보기 위하여 간기능검사와 혈청 NAG 및 PZP 활성도 측정, 그리고 간조직내 교원질함량을 측정하였다. Colchicine을 투여한 경우 사염화탄소 투여로 인한 교원질축적을 현저히 감소시켰으며 혈청 albumin치는 정상대조군과 비슷하였고 혈청 NAG활성도 역시 사염화탄소 투여군보다 현저히 낮은 값을 나타내 보였다. 반면에 아연을 투여한 경우는 실험결과 뚜렷한 효과를 얻을 수 없었다. 결론적으로 colchicine만이 교원질축적 억제효과와 간기능의 보호효과가 있는 것으로 사료된다. Colchicine is a putative antifibrotic agent as it inhibits collagen synthesis and secretion and, also, enhances collagenase activity in vitro. And zinc sulfate has been also known to have an antifibrotic activity in experimental animal models. The aim of this study was to investigate the effects of both high doses of colchicine and zinc sulfate on markers of hepatic fibrosis and on liver function in CCl_4-treated rats. Male Sprague-Dawley rats (100-150g) were divided into 6 groups: control, CCl_4-treated, colchicine treated, colchicine and CCl_4-treated, zinc sulfate treated, zinc sulfate and CCl_4-treated. Colchicine and CCl_4-treated group had significantly lower liver collagen content (0.68±0.13 vs 0.89±0.10mg of hyp./g of wet liver wt., respectively), higher serum albumin level (2.90±0.31 vs 2.47±0.13 g/dl, repectively) and lower serum N-acetyl-β-D-glucos-aminidase activity (22.99±2.76 vs 34.35±9.15 nmole/min/㎖, respectively) than CCl_4-treated group. But zinc sulfate didn't show any remarkable effect in this experiment. In conclusion, high doses of colchicine significantly lowered liver collagen content and improved liver function in CCl_4-treated rats.

Colchicine이 Paraquat에 의한 폐상해에 미치는 영향

김중길,장무웅,곽정식,Kim, Joong-Kil,Chang, Moo-Ung,Kwak, Jyung-Sik 한국현미경학회 2003 Applied microscopy Vol.33 No.4

본 연구는 Paraquat에 의한 폐상해와 colchicine이 paraquat에 의한 폐 섬유화에 미치는 영향을 규명하기 위해 Sprague-Dawley 흰쥐에 10 mg/kg의 paraquat을 2일 간격으로 2회 복강내 투여하였고 다른 군은 2회 투여한 후 1주일에 한번씩 10 mg/kg의 colchicine 을 복강내에 투여하였다. 각 군은 paraquat을 처음 투여한 후 1, 2 및 4 주에 폐를 적출하여 광학 및 전자현미경으로 관찰하였다. 광학현미경 소견은 paraquat 투여 후 1주일 이후에는 폐포벽 및 폐포강에 호중구, 대식세포 및 림프구가 침윤하였다. 그리고 폐포벽에는 시간이 지날수록 세포수가 증식하였다. 그러나 colchicine을 같이 투여한 군에서는 폐포벽의 세포증식이 현저하지 않았다. 전자현미경 소견은 paraquat투여 후 I형 폐포세포와 폐포모세혈관 내피세포의 심한 종창과 탈락이 일어났고 폐포벽에는 호중구, 대식세포 및 단구, 림프구의 침윤이 일어났다. 이러한 소견은 시간이 경과하여도 지속되었다. 섬유아세포의 증식과 교원섬유의 축적은 Paraquat 투여 후 4주 째에 가장 현저하였다. colchicine을 같이 투여한 군에서는 섬유화가 일어났으나 paraquat 단독 투여군보다 심하지는 않았다. 이상의 소견으로 보아 paraquat에 의한 폐상해는 I형 폐포세포와 폐포모세혈관 내피세포가 가장 상해를 잘 받으며 colchicine은 paraquat에 의한 폐섬유화를 억제하는 효과가 있음이 인정된다. This study was undertaken to investigate paraquat-induced pulmonary injuries and effects of colchicine on pulmonary fibrosis by paraquat. Fifteen Sprague-Dawley rats were intraperitoneally injected 10 mg/kg of paraquat and repeatedly with 2 days interval. Another 15 rats were injected paraquat as same manner and simultaneously injected 10 mg/kg of colchicine in a week. Five rats in each group were sacrificed 1, 2, and 4 weeks after initial injections, and lungs extracted were observed by light and electron microscopes. On light microscopy, there was mild infiltration of neutrophils, macrophages, and lymphocytes in alveolar spaces and walls at 1 week after paraquat injection. The cellularity of alveolar wall was increased with time. However, the cellularity was not so prominent in paraquat and colchicine simultaneously injected group. On electron microscopy, there was marked swelling or excoriation of type I epithelial cells and alveolar capillary endothelium with infiltration of neutrophils, macrophages and monocytes, and lymphocytes in alveolar walls. Such findings were persisted with time. In addition, fibroblastic proliferation and deposition of collagen fibers were prominent at 4 weeks after paraquat injection. Fibrosis also occurred at 4 weeks after paraquat and colchicine simultaneous injection. It was not proninent than that of paraquat injected group. According to the above result, it would be concluded that the type I pneumocytes and alveolar capillary endothelial cells are most vulnerable on paraquat poisoning, and that the colchicine is effective on inhibition of paraquat-induced pulmonary fibrosis.

상백피의 colchicine 유도 비만세포 활성화 억제효과

채옥희,이종인,이무삼 대한해부학회 1999 Anatomy & Cell Biology Vol.32 No.5

Colchicine 처리후 흰쥐 뇌에서 Brain-Derived Neurotrophic Factor 면역반응 신경세포의 분포

김정기(Jeong-Ki Kim),박원학(Won-Hark Park),조희중(Hee-Jung Cho) 대한해부학회 1999 Anatomy & Cell Biology Vol.32 No.6

Brain-derived neurotrophic factor (BDNF) mRNA 및 BDNF는 뇌에서 광범위하게 분포함이 밝혀져 있다. BDNF mRNA와 BDNF는 그 분포에 있어서 서로 일치하는 부위가 많지만 그렇지 않은 부위도 많다. 본 연구에서는 BDNF mRNA는 발현되 지만 BDNF가 발현되지 않는 부위에서 BDNF의 발현을 보기 위하여 뇌실에 colchicine을 투여한 후 면역조직화학기법을 시 행한 결과 다음의 사실들을 알 수 있었다. 1. 앞후각핵, 조롱박겉질, 대뇌겉질, 담장, CA2와 CA3의 피라밋층, 치아이랑의 과립세포층, 바닥가쪽편도핵, 가쪽무릎핵, 앞 안쪽시상핵, 앞등쪽시상핵, 뇌실곁시상핵, 뇌실곁시상하부핵 및 배쪽안쪽시상하부핵에서는 colchicine 비처리군에 비하여 BDNF 면역반응 신경세포가 증가하였다. 2. CA1의 피라밋층, A1, A2, A4-A10 세포군, C1-C3 세포군, 큰솔기핵, 가쪽거대세포핵 및 척수안뜰신경핵에서는 colchicine 처리 후 새로이 많은 BDNF 면역반응 신경세포가 관찰되었다. 이상의 결과는 colchicine 처리 후 흰쥐 뇌에서 BDNF 함유 신경세포들은 그 분포에 있어서 BDNF mRNA 함유 신경세포 와 일치함을 알 수 있었다. Widespread brain-derived neurotrophic factor (BDNF) mRNA and protein expression has been detected in the brain. Despite substantial overlap between BDNF mRNA and protein expression, there is general anatomical regions, where there is discordance of these expression. We performed, therefore, immunohistochemistry after colchicine treatment into the ventricle to evaluate the possible presence of BDNF-immunoreactive (IR) in the regions where BDNF mRNA was expressed, but not BDNF-IR. The results obtained were as follows; There was substantial increase in the number of BDNF-IR neurons in the anterior olfactory nucleus, the piriform cortex, the cerebral cortex, the claustrum, the stratum pyramidale of the CA2 and the CA3, the granule cell layer of the dentate gyrus, the basolateral amygdaloid nucleus, the lateral geniculate nucleus, the anteromedial thalamic nucleus, the anterodorsal thalamic nucleus, the paraventricular thalamic nucleus, the paraventricular hypothalamic nucleus and the ventromedial hypothalamus nucleus, compared to the same brain area of non-colchicine treated rat. We detected many new BDNF-IR neurons in the stratum pyramidale of the CA1, A1, A2, A4-A10 cell groups, C1-C3 cell groups, the raphe magnus nucleus, the lateral paragigantocellular nucleus and the spinal vestibular nucleus. The results show that the localization of BDNF-IR neurons after colchicine treatment is consistant with that of BDNF mRNA containing neurons in the brain.

Colchicine 처리 후 흰쥐 뇌에서 Brain-Derived Neurophic Factor 면역 반응 신경세포의 분포

김정기,조희중,박원학 대한해부학회 1999 Anatomy & Cell Biology Vol.32 No.6

Colchicine 처리후 흰쥐 뇌에서 Brain-Derived Neurotrophic Factor 면역반응 신경세포의 분포

김정기,박원학,조희중 경북대학교 병원 2001 경북대학교병원의학연구소논문집 Vol.5 No.1

Brain-derived neurotrophic factor(BDNF) mRNA 및 BDNF는 뇌에서 광범위하게 분포함이 밝혀져 있다.BDNF mRNA와 BDNF는 그 분포에 있어서 서로 일치하는 부위가 많지만 그렇지 않은 부위도 있다. 본 연구에서는 BDNF mRNA는 발현되지만 BDNF가 발현되지 않는 부위에서 BDNF의 발현을 보기 위하여 뇌실에 colchicine을 투여한 후 면역조직화학기법을 시행한 결과 다음의 사실을 알 수 있었다. 1.앞후각핵, 조롱박겉질, 대되겉질,담장,CA2와 CA3의 피라밋충, 치아이랑의 과립세포층, 바닥가쪽 편도핵, 가쪽무릎핵, 앞안쪽시상핵,뇌실곁시상핵,뇌실곁시상하부핵 및 배쪽안쪽시상하부핵에서는 colchicine비처리군에 비하여 BDNF면역반응 신경세포가 증가하였다. 2. CA1의 피라밋충,A1,A2,A4-A10세포군, 큰솔기핵, 가쪽거대세포핵 및 척수안뜰신경핵에서는 colchicine처리 후 새로이 많은 BDNF면역반응 신경세포가 관찰되었다. 이상의 결과는 colchicine처리 후 흰쥐 뇌에서 BDNF함유 신경세포들은 그 분포에 있어서 BDNF mRNA함유 신경세포와 일치함을 알 수 있었다. Widespread brain-derived neurotrophic factor(BDNF) mRNA and protein expression has been detected in the brain.Despite substantial overlap between BDNF mRNA and protein expression, there is general anatomical regions, where there is discordance of these expression.We performed, therefore, immunohistochemistry after colchicine treatment into the ventricle to evaluate the possible presence of BDNF-immunoreactive(IR)in the regions where BDNF mRNA was expressed, but not BDNF-IR . The results obstained were as folloes; There was substantial increase in the number of BDNF-IR neurons in the anterior olfactory nucleus, the piriform cortex, the cerebral cortex, the claustrum, the stratum pyramidate of the CA2 and the CA3, the granule cell layer of the dentate gyrus, the basolateral amygdaloid nucleus, the lateral geniculate nucleus, the anteromedial thalmic nucleus,the anterodorsal thalamic nucleus, the paraventricular thalamic nucleus, the paraventricular hypothalamic nucleus and the ventromedial hypothalamic nucleus, compared to the same brain area of non-colchicine treated rat.We detected many new BDNF-IR neurons in the stratum pyramidale of the CA1, A1, A2,A4-A10 cell groups, C1-C3 cell groups, the raphe magnus nucleus, the lateral paragigantocellular nucleus and the spinal vestibular nucleus. The results show that the localization of BDNF-IR neurons after colchicine treatment is consistant with that of BDNF mRNA containing neurons in the brain.

만성 간질환 환자에서 콜히친 약리효과와 T1-201 간문맥 스캔 단락지수와의 관련성

윤창옥,강문수,변재원,고동희,김동욱,최윤영,강주섭,이민호,곽민정 大韓臨床藥理學會 2001 臨床藥理學會誌 Vol.9 No.1