이 작품은 국립 보건원, 국립 일반 의학 과학 (R01GM063075)의 연구소 보완 및 대체 의학의 국립 센터 (R01AT05076)에서 교부금에 의해 지원되었다.

1. 패혈증의 동물 모델의 확립 <ol><li> 마우스는 케타민 (75 밀리그램 / kg, 근육내, IM) 및 xylazine (10 밀리그램 / kg, IM)와 anesthetized하며, 나태한 자리에 서있는. </li><li> 안정적인 지위를 보장하기 위해 테이프로 마우스의 발을 고쳐. </li><li> betadine이나 기타 피부 소독제 및 알코올 3 교대 스크럽으로 복부를 청소합니다. 다음 15 밀리미터 중간선 절개는이게 맹장을 폭로합니다. </li><li> 대변​​의 압출 수 있도록 22 게이지 바늘로 한 번 출혈도 잡았 cecal 몸통 cecal 끝부분에서 약 5.0 mm에서 4-0 실크 봉합사로이게 맹장을 Ligate 후 펑크. </li><li> 이게 맹장은 즉시 정상 내부 복부 위치로 다시 바뀝니다. </li><li> 첫째 흡수성 봉합과 복부의 근육을 폐쇄하고 상처 클립이나 nonabsorbable 봉합과 피부를 닫아 두 레이어에 절개 사이트를 닫습니다. </li><li> 0.5 ML 정상적인 생리 식염수로 마우스를 소생과 단일 할즉시 수술의 완료 후 imipenem의 SE (subcutaneously 0.5 밀리그램 / 마우스). </li><li> 음식과 물을 무료로 이용 깨끗한 새장에 다시 마우스를 반환합니다. </li><li> 다양한 시간 포인트 포스트 CLP에서 허브 추출물 또는 구성 요소 intraperitoneally을 관리합니다. </li><li> 동물의 생존은 세 개 이상의 주 동안 감시하고 있습니다. 서서하는 어려움, 사망 전 호흡, 심한 근육 위축 및 통제 출혈을 전시 죽어가는 동물은 과다 복용 이산화탄소 흡입으로 euthanized해야합니다. </li><li> 그것은 시토킨 수준을 순환하는 것은 이러한 연구에 중요한 파라미터 점에 유의하는 것이 중요합니다. 각종 진통제는 시토킨 릴리스와 활동에 영향을 표시했습니다, 따라서 의도적으로 수술 후 치료를 피할 수있다. </li></ol> 2. 허벌 추출의 작성 <ol><li> 1-4 시간 (나뭇잎을위한 1 시간, 그리고 뿌리를위한 4 시간)에 대해 뜨거운 물 (85 ​​° C)의 허브를 추출합니다. </li><li> 물 정도 원심 분리기luble 분수 (3,300그램, 20 분, 4 ℃) 불용성 입자를 제거합니다. </li><li> 여과액 0.2 μm의 필터를 통해 뜨는 분수. </li><li> 맑은 수용성 여과물 분율 다음 Centriprep YM-10 원심 필터 (카탈로그 안돼. 4,305, Millipore)를 사용하여 ultrafiltration fractionated입니다. </li><li> 은 (&lt;10 kDa와 높은 (10 kDa) 낮은)&gt; 분자량의 분수 (MWF)는 대식 세포 문화를 사용하는 HMGB1-억제 활동을 심사하고 결과. </li><li> 24 시간 포스트 CLP에서 HMGB1-억제 허브 추출물 또는 구성 요소의 Intraperitoneal 행정부는 그들의 치료 효능을 평가합니다. </li></ol> 3. 복막 대식 세포 격리 <ol><li> Thioglycollat​​e 국물 (4 %, 2.0 ML)는 정상 생쥐에 intraperitoneally을 관리합니다. </li><li> 기본 복막 macrophages는 이전에 10의 설명에 따라 3 일 수확하고 있습니다. </li><li> Macrophages 1과 보충 DMEM 배지 (Gibco BRL, 그랜드 아일랜드, 뉴욕)에서 사전 교양입니다0% 태아 소 혈청 (FBS), 2 mmol / L 글루타민, 그리고 1퍼센트 페니실린. </li><li> 자기편 macrophages는 가볍게에서 함께 씻어과 교양되며, 혈청 프리 이시간 박테리아 내독소로 자극하기 전에 OPTI-MEM 나는 매체 (lipopolysaccharide, LPS, E. 대장균 0111 : B4, 시그마 - 올드 리치). </li><li> LPS의 자극 후 16시간에서 문화 매체에서 HMGB1의 수준은 서양의 모래 바닥은 분석 11 시까지 결정됩니다. </li><li> 상대 밴드 강도가 HMGB1 투석을 함께 생성되는 표준 곡선에 대한 참조로 HMGB1 수준을 결정하기 위해 NIH 이미지에게 1.59 소프트웨어를 사용하여 계량되었다. </li></ol> 4. 대표 결과 1. CLP은 조직과 지역 염증을 유도합니다. CLP 수술 몇 시간 내에 동물 piloerection, 혼수, huddling, 그리고 음식과 물을 섭취의 감소를 포함 패혈증의 임상 증상을 보이기. 연속 체계적으로 심한 복막염을 개발하는 동물96 HR - 감염은 일반적으로 48 이내에 죽어. 그러나, 심지어는 나이, 성별 -, 그리고 유전적 배경 - 유사한 동물 실험 패혈증의 과정에서 특이한 방식으로 수술을 CLP에 응답할 수 있습니다. 어떤 동물이 죽어가는 상태 (그림 1에 정의된) 접근했을 수도 있지만 예를 들어, 48 시간 포스트 CLP에서, 다른 사람이 아닌 죽어가는 상태에서 남아있을 수 있습니다. 순환 크린 시토킨의 종합 설문 조사는 죽어가는가 아닌 죽어가는 상태 (그림 1) 12의 생쥐간에 여러 크린 시토킨 수준의 극적인 차이 (예, IL-6, KC, MIP-2 및 sTNFR1)을 공개했다. 그들의 순환 수준 실험 또는 임상 12-14 패혈증 15 치명적인 결과의 신뢰성 predictors이기 때문에 특히, 이러한 염증 중재자는 패혈증의 대리 마커로 분류되었습니다. 또한, CLP는 또한 다양한 프로와 안티 - 염증 크린 시토킨 및 chemokines의 지역 릴리스를 유도. 에서, 예를 들어48 시간 포스트 CLP, 중요한 크린 시토킨의 금액 (예, IL-6)과 chemokines은 (KC와 MIP-2) 아직 또한 로컬 복막 세척 유체 (그림 2) 혈액뿐만 아니라 systemically 측정하지만 수 있습니다. 2. HMGB1-억제 허브 추출물 또는 구성 요소에 대한 심사. 대식 세포 배양을 사용하여, 우리는 억제 내독소 - 유도된 HMGB1 자료의 다양한 허브 추출물 또는 구성 요소의 용량 (그림 3)을 평가할 수 있었다. 억제 HMGB1 자료들의 능력에 비추어, 우리는 더 이상 동물 모델 패혈증에 그들의 효능을 탐험. 시점 쥐가 혼수, 설사, 그리고 piloerection 포함한 패혈증의 명백한 징후를 개발 - 실험적 패혈증 8 HMGB1 축적의 후반과 연장 속도론을 감안할 때, HMGB1 억제제의 처음 복용량은 패혈증의 발병 후 24 시간이 주어졌다. 마찬가지로 그림 4에 표시된 지연 및 주요 녹차 광고의 반복 관리omponent, epigallocatechin-3-gallate (EGCG)가 패혈증의 발병 후 24 H 시작하여 상당히 치명적인 패혈증 12 쥐를 구출. 구두로 주어진 경우에도 크게 16 % 아래로 44% 16 일부터 동물의 생존 속도를 증가, 치명적인 패혈증에서 여전히 구출 쥐를 EGCG. 그것은 여러 허브 구성 요소를 사용하여 조합 요법이 패혈증의 동물 모델에서 상당한 더 나은 보호를 달성할 수 있는지 여부를 확인하는 것이 중요 것입니다. 함께 촬영 이러한 실험 데이터는 CLP-유도된 패혈증의 동물 모델을 사용하여 화면에 소설 치료 중개사에게 우리의 접근 방식을 검증. 5. 대표 결과 <img alt="그림 1" src="/files/ftp_upload/3926/3926fig1.jpg" /> 1 그림. 대리모 마커의 순환 수준은 죽어가는 상태에 접근 패혈증에 의한 동물에 극적으로 높아집니다. Balb / C 마우스는 CLP에 의해 패혈증 들어서는과 질병의 징후의 발전을 위해 감시되었다. 에서패혈증 (52 HR 게시물 CLP)의 늦은 단계는 혈액 3 정상 생쥐 (-CLP), 죽어가는 상태를 접근 3 정화조 마우스, 그리고 비 죽어가는 상태에서 3 패혈증에 의한 생쥐로부터 수집되었다. 세럼은 각 그룹에서 풀링하고, 항체 어레이에 의​​한 시토킨 프로필 assayed되었다. 서로 다른 그룹 간의 여러 대리모 마커의 상대적인 수준의 극적인 차이를 확인합니다. 제작사로부터 부여된 허가 10.1371/journal.pone.0001153.g006 : 간접 자원부에서 적응. <img alt="그림 2" src="/files/ftp_upload/3926/3926fig2.jpg" /> 그림 2. 48 시간 포스트 CLP. Balb / C 마우스에서 로컬 및 체계적 크린 시토킨 및 chemokines의 감지는 CLP에 의해 패혈증를 받게되었으며, 혈액 또는 복막 액은 48 H 포스트 CLP에서 수확했다. 여러 크린 시토킨 및 풀링된 혈청이나 복막 세척 유체의 chemokines의 상대적 수준은 시토킨 항체 어레이로 측정하고, 임의의 단위 (AU)으로 표현되었다. 컨트롤, 혈액 및 복막 유체 SA로mples은 개복술없이 정상적인 건강한 동물 (-CLP)에서 얻은되었다. <img alt="그림 3" src="/files/ftp_upload/3926/3926fig3.jpg" /> 그림 3. 허벌 구성 요소는 선량 - dependently 기본 대식 세포 배양에서 내독소 - 유도된 HMGB1 릴리스를 저해. 차 murine 복막 macrophages는 부재의 LPS, 또는 한방 구성 요소의 존재 (예, EGCG, 15 μm의)을 자극했다. LPS의 자극 후 16시간에서 문화 매체에서 HMGB1의 수준은 서양의 모래 바닥 분석에 의해 결정됩니다. 제작사로부터 부여된 허가 10.1371/journal.pone.0001153.g006 : 간접 자원부에서 적응. <img alt="그림 4" src="/files/ftp_upload/3926/3926fig4.jpg" /> 4 그림. 허벌 구성 요소가 Balb / C 마우스는 CLP에 의해 치명적인 패혈증를 받게되었다. 치명적인 패혈증에서 마우스를 구출하고, 한방 성분 (EGCG)가 24에서 시행 intraperitoneally 있었는데, 48, 72시간는 패혈증의 발병을 게시할 수 있습니다.imal 생존는 2 주 동안 감시했다. 카플란 - 마이어 방법은 그룹 간의 사망률 속도의 차이를 비교하기 위해 사용되었다. *, P &lt;0.05 염분 대. 제작사로부터 부여된 허가 10.1371/journal.pone.0001153.g006 : 간접 자원부에서 적응.

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C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Passive+immunization+against+cachectin/tumor+necrosis+factor+protects+mice+from+lethal+effect+of+endotoxin.">Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.</a> Science. 229, 869-871 (1985).</li><li>Tracey, K. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anti-cachectin/TNF+monoclonal+antibodies+prevent+septic+shock+during+lethal+bacteraemia.">Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia.</a> Nature. 330, 662-664 (1987).</li><li>Eskandari, M. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Anti-tumor+necrosis+factor+antibody+therapy+fails+to+prevent+lethality+after+cecal+ligation+and+puncture+or+endotoxemia.">Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia.</a> J. Immunol. 148, 2724-2730 (1992).</li><li>Ziegler, E. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+gram-negative+bacteremia+and+septic+shock+with+HA-1A+human+monoclonal+antibody+against+endotoxin.+A+randomized,+double-blind,+placebo-controlled+trial.+The+HA-1A+Sepsis+Study+Group.">Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group.</a> N. Engl. J. Med. 324, 429-436 (1991).</li><li>Ziegler, E. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Treatment+of+gram-negative+bacteremia+and+shock+with+human+antiserum+to+a+mutant+Escherichia+coli.">Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli.</a> N. Engl. J. Med. 307, 1225-1230 (1982).</li><li>Abraham, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficacy+and+safety+of+monoclonal+antibody+to+human+tumor+necrosis+factor+alpha+in+patients+with+sepsis+syndrome.+A+randomized,+controlled,+double-blind,+multicenter+clinical+trial.+TNF-alpha+MAb+Sepsis+Study+Group.">Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group.</a> JAMA. 273, 934-941 (1995).</li><li>Cohen, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Adjunctive+therapy+in+sepsis:+a+critical+analysis+of+the+clinical+trial+programme.">Adjunctive therapy in sepsis: a critical analysis of the clinical trial programme.</a> Br. Med. Bull. 55, 212-225 (1999).</li><li>Dellinger, R. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Surviving+Sepsis+Campaign:+international+guidelines+for+management+of+severe+sepsis+and+septic+shock:+2008.">Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008.</a> Crit. Care Med. 36, 296-327 (2008).</li><li>Wang, H., Zhu, S., Zhou, R., Li, W., Sama, A. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Therapeutic+potential+of+HMGB1-targeting+agents+in+sepsis.">Therapeutic potential of HMGB1-targeting agents in sepsis.</a> Expert. Rev. Mol. Med. 10, e32 (2008).</li><li>Wang, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+aqueous+extract+of+a+popular+herbal+nutrient+supplement,+Angelica+sinensis,+protects+mice+against+lethal+endotoxemia+and+sepsis.">The aqueous extract of a popular herbal nutrient supplement, Angelica sinensis, protects mice against lethal endotoxemia and sepsis.</a> J. Nutr. 136, 360-365 (2006).</li><li>Li, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+cardiovascular+drug+rescues+mice+from+lethal+sepsis+by+selectively+attenuating+a+late-acting+proinflammatory+mediator,+high+mobility+group+box+1.">A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.</a> J. Immunol. 178, 3856-3864 (2007).</li><li>Fukuyama, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mixed+bacterial+infection+model+of+sepsis+in+rabbits+and+its+application+to+evaluate+superantigen-adsorbing+device.">Mixed bacterial infection model of sepsis in rabbits and its application to evaluate superantigen-adsorbing device.</a> Blood Purif. 23, 119-127 (2005).</li></ol>

AES와 HW는 패혈증에 대한 잠재적인 치료 대리인으로서 HMGB1 억제제 (tanshinones) 관련 특허 출원의 공동 발명가입니다.

실험실에서는 패혈증의 여러 동물 모델은 잠재적인 소설 요법을 개발하기 위해서는 패혈증의 pathogenesis을 이해하는 고용되었습니다. 그들의 임상적 관련 성은 패혈증에 대한 임상 응용에 대한 동물 연구의 성공적인 번역을하기 전에 논쟁의 대상이 남아있다. 조기 크린 시토킨에 대한 중화 항체 (예 : TNF)는 bacteremia / endotoxemia 17,18의 동물 모델에서 보호했지만, 그들은 실제로 패혈증 19<...

<table border="1"><tbody><tr><td> 시약의 이름 </td><td> 회사 </td><td> 카탈로그 번호 </td></tr><tr><td> Betadine </td><td> 퍼듀 제품 LP </td><td> 25655-41-8 </td></tr><tr><td> imipenem </td><td> 머크 &amp; 유한 주식 회사 </td><td> 9,882,821 </td></tr><tr><td> 케타민을 HCL </td><td> Hospira 주식 회사 </td><td> RL-0065 </td></tr><tr><td> Xylazine </td><td> 로이드 연구소 </td><td> 4821 </td></tr><tr><td> Autoclip </td><td> Becton 디킨슨 </td><td> 427,631 </td></tr><tr><td> 4-0 실크 봉합사 </td><td> Roboz </td><td> SUT-15-2 </td></tr><tr><td> Surflo IV 카테터 </td><td> Terumo </td><td> SR * OX2419CA </td></tr><tr><td> RayBio 마우스 시토킨 항체 어레이 </td><td> RayBiotech 주식 회사 </td><td> AAM-CYT-3 </td></tr><tr><td> Thioglycollat​​e </td><td> Becton 디킨슨 </td><td> 211,716 </td></tr></tbody></table>

use of animal model of sepsis to evaluate novel herbal therapies

패혈증은 미생물 감염으로 인한 전신 염증 반응 증후군을 말합니다. 그것은 외인성 세균 독소 (endotoxemia) 또는 박테리아 (bacteremia)의 주입뿐만 아니라 cecal 내고 주사 (CLP) 1-3 의해이게 맹장의 수술 천공 등 여러 가지 기법에 의해 동물에서 정기적으로 모의하고있다. CLP는 다공 맹장염 또는 diverticulitis의 인간 임상 질환을 흉내낸, 박테리아의 spillage 및 복막 캐비티의 배설물로 오염 수 있습니다. 같은 최종 사망률 속도에 의해 반영 패혈증의 심각도는, cecal 찔린 2 사용 바늘의 크기를 변화하여 수술 제어할 수 있습니다. 인간의 패혈증 3의 임상 과정 동안 지켜봤을 때 동물에서는 CLP는 심장 혈관 신진 대사와 면역 반응과 유사, biphasic hemodynamic을 유도합니다. 따라서 CLP 모델은 1-3 실험적인 패혈증에 가장 임상적으로 관련성이 높은 모델 중 하나로 간주됩니다. &lt;이/ P&gt; 다양한 동물 모델 실험적인 패혈증의 pathogenesis의 기본 복잡한 메커니즘을 명료하게하다하는 데 사용되었습니다. 패혈증의 치명적인 결과가 조기 크린 시토킨의 과도한 축적 4-6과 늦은 전염증성 중재자 (예 : HMGB1) 7 (예 : TNF, IL-1과 IFN-γ 등)에 부분적으로 기인 것입니다. 초기 전염증성 크린 시토킨와 비교할 때, 늦게 연기 중재자는 임상 애플 리케이션을위한 광범위한 치료 창이 있습니다. 예를 들어, CLP 후 24 시간을 시작 HMGB1 - 중화 항체의 지연 행정부는 여전히 치명적인 패혈증의 늦은 중재자로 HMGB1를 설립, 주죠 8,9에서 쥐를 구출. 늦은 연기 중재자로서 HMGB1의 발견 중국어 허벌 의학을 사용하여 패혈증 요법의 발전을위한 조사의 새로운 분야를 시작했습니다. 본 논문에서 우리는 HM에 대한 한방 의학을 심사한에서 CLP 유도된 패혈증의 절차를 설명하며 사용치료를 GB1 타겟팅.

Watch this Scientific Journal Video about Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies at JoVE.com

Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies

패혈증은 미생물 감염으로 인한 전신 염증 반응 증후군을 참조하고, cecal 내고 주사 (CLP)을 되나 수술 기법에 의한 시뮬레이션이 될 수 있습니다. 여기 치료 대리인을위한 약초를 구분할 CLP 유발 동물 모델을 사용하는 방법을 설명합니다.

소설 허벌 요법을 평가하는 패혈증의 동물 모델의 사용

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. It has been routinely simulated in animals by several ...

use-of-animal-model-of-sepsis-to-evaluate-novel-herbal-therapies

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19.3K 조회수.  North Shore – LIJ Health System. 패혈증은 미생물 감염으로 인한 전신 염증 반응 증후군을 참조하고, cecal 내고 주사 (CLP)을 되나 수술 기법에 의한 시뮬레이션이 될 수 있습니다. 여기 치료 대리인을위한 약초를 구분할 CLP 유발 동물 모델을 사용하는 방법을 설명합니다.

비디오: Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies

The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice

Autoimmune hepatitis is a rare but life threatening autoimmune disease of the liver of unknown etiology1,2. In the past many attempts have been made to generate an animal model that reflects the characteristics of the human disease 3-5. However, in various models the induction of disease was rather complex and often hepatitis was only transient3-5. Therefore, we have developed a straightforward mouse model that uses the major human autoantigen in type 2 autoimmune hepatitis (AIH-2), namely hCYP2D6, as a trigger6. Type 1 liver-kidney microsomal antibodies (LKM-1) antibodies recognizing hCYP2D6 are the hallmark of AIH-27,8. Delivery of hCYP2D6 into wildtype FVB or C57BL/6 mice was by an Adenovirus construct (Ad-2D6) that ensures a direct delivery of the triggering antigen to the liver. Thus, the ensuing local inflammation generates a fertile field9 for the subsequent development of autoimmunity. A combination of intravenous and intraperitoneal injection of Ad-2D6 is the most effective route to induce a long-lasting autoimmune damage to the liver (section 1). Here we provide a detailed protocol on how autoimmune liver disease is induced in the CYP2D6 model and how the different aspects of liver damage can be assessed. First, the serum levels of markers indicating hepatocyte destruction, such as aminotransferases, as well as the titers of hCYP2D6 antibodies are determined by sampling blood retroorbitaly (section 2). Second, the hCYP2D6-specific T cell response is characterized by collecting lymphocytes from the spleen and the liver. In order to obtain pure liver lymphocytes, the livers are perfused by PBS via the portal vein (section 3), digested in collagen and purified over a Percoll gradient (section 4). The frequency of hCYP2D6-specific T cells is analyzed by stimulation with hCYP2D6 peptides and identification of IFN&gamma;-producing cells by flow cytometry (section 5). Third, cellular infiltration and fibrosis is determined by immunohistochemistry of liver sections (section 6). Such analysis regimen has to be conducted at several times after initiation of the disease in order to prove the chronic nature of the model. The magnitude of the immune response characterized by the frequency and activity of hCYP2D6-specific T and/or B cells and the degree of the liver damage and fibrosis have to be assessed for a subsequent evaluation of possible treatments to prevent, delay or abrogate the autodestructive process of the liver.

Infection of mice with an Adenovirus expressing the major human autoantigen cytochrome P450 2D6 (hCYP2D6) recognized by sera of patients suffering from type 2 autoimmune hepatitis results in a persistent form of autoimmune-mediated liver disease characterized by extensive hepatitis, fibrosis and generation of a CYP2D6-specific immune response.

CYP2D6 동물 모델 : 마우스에 면역 간염을 유발하는 방법

Autoimmune hepatitis is a rare but life threatening autoimmune disease of the liver of unknown etiology1,2. In the past many attempts have been made to ...

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A Mouse Tumor Model of Surgical Stress to Explore the Mechanisms of Postoperative Immunosuppression and Evaluate Novel Perioperative Immunotherapies

Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to the development of metastatic disease in animal models and in cancer patients. Preclinical work from our group and others has demonstrated a profound suppression of innate immune function, specifically NK cells in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Relatively few animal studies and clinical trials have focused on characterizing and reversing the detrimental effects of cancer surgery. Using a rigorous animal model of spontaneously metastasizing tumors and surgical stress, the enhancement of cancer surgery on the development of lung metastases was demonstrated. In this model, 4T1 breast cancer cells are implanted in the mouse mammary fat pad. At day 14 post tumor implantation, a complete resection of the primary mammary tumor is performed in all animals. A subset of animals receives additional surgical stress in the form of an abdominal nephrectomy. At day 28, lung tumor nodules are quantified. When immunotherapy was given immediately preoperatively, a profound activation of immune cells which prevented the development of metastases following surgery was detected. While the 4T1 breast tumor surgery model allows for the simulation of the effects of abdominal surgical stress on tumor metastases, its applicability to other tumor types needs to be tested. The current challenge is to identify safe and promising immunotherapies in preclinical mouse models and to translate them into viable perioperative therapies to be given to cancer surgery patients to prevent the recurrence of metastatic disease.

A mouse tumor model of surgical stress is used to explore how postoperative immune suppression promotes metastatic disease and to evaluate immunostimulatory perioperative therapies.

수술 후 면역 억제의 메커니즘을 탐색 소설 수술 전후 면역 요법을 평가하기 위해 수술 스트레스의 마우스 종양 모델

Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to ...

Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Bladder cancer is one of the most common malignancies of the urogenital tract. Intravesical injection of Bacillus Calmette-Gu&#233;rin (BCG) is the gold standard treatment for the high-grade non-muscle invasive bladder cancer (NMIBC). However, since the treatment-related side effects are relevant, newer biological response modifiers with a better benefit/side effects ratio are needed.
The tumour microenvironment can influence both tumour development and therapy efficacy. In order to obtain a good model, it is desirable to implant tumour cells in the organ from which the cancer originates.
In this protocol, we describe a method for establishing a tumour in the bladder cavity of female mice and subsequent delivery of therapeutic agents; the latter are exemplified by our use of Helicobacter pylori neutrophil activating protein (HP-NAP). A preliminary chemical burn of the mucosa, followed by the injection of mouse urothelial carcinoma cell line MB49 via urethral catheterization, enables the cells to attach to the bladder mucosa. After a period, required to allow an initial proliferation of the cells, mice are treated with HP-NAP, administrated again via catheterization. The anti-tumour activity of HP-NAP is evaluated comparing the tumour volume, the extent of necrosis and the degree of vascularization between vehicle- and HP-NAP-treated animals.

Evaluation of the Efficacy of the H. pylori Protein HP-NAP as a Therapeutic Tool for Treatment of Bladder Cancer in an Orthotopic Murine Model

Here the method to establish a syngeneic mouse model of orthotopic bladder tumour to evaluate the anti-tumour efficacy of the bacterial protein HP-NAP is described.

효능 평가<em&gt; H. 파이로리</em동소 이식 쥐 모델에서 방광암의 치료를위한 치료 도구로&gt; 단백질 HP-NAP

Bladder cancer is one of the most common malignancies of the urogenital tract. Intravesical injection of Bacillus Calmette-Gu&#233;rin (BCG) is the gold ...

Bioluminescence Imaging of an Immunocompetent Animal Model for Glioblastoma

In contrast to commonly reported human glioma xenograft animal models, GL261 murine glioma xenografts recapitulate nearly all relevant clinical and histopathologic features of the human disease. When GL261 cells are implanted intracranially in syngeneic C57BL/6 mice, the model has the added advantage of maintaining an intact immune microenvironment. Stable expression of luciferase in GL261 cells allows non-invasive cost effective bioluminescence monitoring of intracranial tumor growth. We have recently demonstrated that luciferase expression in GL261 cells does not affect the tumor growth properties, tumor cell immunomodulatory cytokine expression, infiltration of immune cells into the tumor, or overall survival of animals bearing the intracranial tumor. Therefore, it appears that the GL261 luciferase glioma model can be useful in the study of novel chemotherapeutic and immunotherapeutic modalities. Here we report the technique for generating stable luciferase expression in GL261 cells and how to study the in vitro and in vivo growth of the tumor cells by bioluminescence imaging.

GL261 glioma cells provide a useful immunocompetent animal model of glioblastoma. The goals of this protocol are to demonstrate proper techniques for monitoring intracranial tumor growth using in vivo bioluminescence imaging, and to verify the utility of luciferase-modified GL261 cells for studying tumor immunology and immunotherapeutic approaches for treating glioblastoma.

교 모세포종에 대한 면역 적격 동물 모델의 생물 발광 영상

In contrast to commonly reported human glioma xenograft animal models, GL261 murine glioma xenografts recapitulate nearly all relevant clinical and ...

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, normothermic ex vivo liver perfusion (NEVLP) has been introduced as a method to evaluate and modify organ function. NEVLP has many advantages in comparison to hypothermic and subnormothermic perfusion including reduced preservation injury, restoration of normal organ function under physiologic conditions, assessment of organ performance, and as a platform for organ repair, remodeling, and modification. Both murine and porcine NEVLP models have been described. We demonstrate a rat model of NEVLP and use this model to show one of its important applications &#8212; the use of a therapeutic molecule added to liver perfusate. Catalase is an endogenous reactive oxygen species (ROS) scavenger and has been demonstrated to decrease ischemia-reperfusion in the eye, brain, and lung. Pegylation has been shown to target catalase to the endothelium. Here, we added pegylated-catalase (PEG-CAT) to the base perfusate and demonstrated its ability to mitigate liver preservation injury. An advantage of our rodent NEVLP model is that it is inexpensive in comparison to larger animal models. A limitation of this study is that it does not currently include post-perfusion liver transplantation. Therefore, prediction of the function of the organ post-transplantation cannot be made with certainty. However, the rat liver transplant model is well established and certainly could be used in conjunction with this model. In conclusion, we have demonstrated an inexpensive, simple, easily replicable NEVLP model using rats. Applications of this model can include testing novel perfusates and perfusate additives, testing software designed for organ evaluation, and experiments designed to repair organs.

A Small Animal Model of Ex Vivo Normothermic Liver Perfusion

There is a significant liver donor shortage, and criteria for liver donors have been expanded. Normothermic ex vivo liver perfusion (NEVLP) has been developed to evaluate and modify organ function. This study demonstrates a rat model of NEVLP and tests the ability of pegylated-catalase, to mitigate liver preservation injury.

Ex Vivo Normothermic 간 관류의 작은 동물 모델

There is a significant shortage of liver allografts available for transplantation, and in response the donor criteria have been expanded. As a result, ...

Isometric Contractility Measurement of the Mouse Mesenteric Artery Using Wire Myography

The wire myograph technique is used to assess the contractility of vascular smooth muscles in response to depolarization, GPCR agonists/inhibitors and drugs. It is widely used in many studies on the physiological functions of vascular smooth muscle, the pathogenesis of vascular diseases such as hypertension, and the development of smooth muscle relaxant drugs. The mouse is a widely used model animal with a large pool of disease models and genetically modified strains. We introduced this method to measure the isometric contraction of mouse mesenteric artery in detail. A 1.4-mm segment of mouse mesenteric resistance artery was isolated and mounted on a myograph chamber by passing two steel wires through its lumen. After equilibration and normalization steps, the vessel segment was potentiated by a high-K+ solution twice prior to the contraction assay. As an example of the application of this method in drug development, we measured the relaxant effect of a novel natural substance, neoliensinine, isolated from a Chinese herb, embryos of the lotus seed (Nelumbo nucifera Gaertn.) on mouse mesenteric arteries. The vessel segments mounted on the myograph chamber were stimulated with a high-K+ solution. When the force tension reached a stable sustained phase, cumulative doses of neoliensinine were added to the chamber. We found that neoliensinine had a dose-dependent relaxant effect on smooth muscle contraction, thus suggesting that it bears potential activity against hypertension. In addition, as the vessel segment can survive at least 4 hours after mounting and maintain contractility induced by the high-K+ solution for many times, we suggest that the wire myograph system may be used for the time-consuming process of drug screening.

The wire myograph technique is used to investigate vascular smooth muscle functions and screen new drugs. We report a detailed protocol for measuring the isometric contractility of the mouse mesenteric artery and for screening new relaxants of vascular smooth muscle.

Myography 와이어를 사용 하 여 마우스 Mesenteric 동맥의 isometric 수축 측정

The wire myograph technique is used to assess the contractility of vascular smooth muscles in response to depolarization, GPCR agonists/inhibitors and ...

Novel Methods for Intranasal Administration Under Inhalation Anesthesia to Evaluate Nose-to-Brain Drug Delivery

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain barrier. However, there have been few reports regarding not only the quantitative analysis but also optimal administration conditions and dosing regimens for investigations of nose-to-brain delivery. The limited progress in research on nose-to-brain pathway mechanisms using rodents represents a significant impediment in terms of designing nose-to-brain delivery systems for candidate drugs.
To gain some headway in this regard, we developed and evaluated two novel methods of stable intranasal administration under inhalation anesthesia for experimental animals. We also describe a method for the evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radio-labeled [14C]-inulin (molecular weight: 5,000) as a model substrate of water-soluble macromolecules.
Initially, we developed a pipette-based intranasal administration protocol using temporarily openable masks, which enabled us to perform reliable administration to animals under stable anesthesia. Using this system, [14C]-inulin could be delivered to the brain with little experimental error.
We subsequently developed an intranasal administration protocol entailing reverse cannulation from the airway side through the esophagus, which was developed to minimize the effects of mucociliary clearance (MC). This technique led to significantly higher levels of [14C]-inulin, which was quantitatively detected in the olfactory bulb, cerebrum, and medulla oblongata, than the pipette method. This appears to be because retention of the drug solution in the nasal cavity was substantially increased by active administration using a syringe pump in a direction opposite to the MC into the nasal cavity.
In conclusion, the two methods of intranasal administration developed in this study can be expected to be extremely useful techniques for evaluating pharmacokinetics in rodents. The reverse cannulation method, in particular, could be useful for evaluating the full potential of nose-to-brain delivery of drug candidates.

Here, we describe two novel methods of stable intranasal administration under inhalation anesthesia with minimal physical stress for experimental animals. We also describe a method for quantitative evaluation of drug distribution levels in the brain via the nose-to-brain pathway using radiolabeled [14C]-inulin as a model substrate of water-soluble macromolecules.

Intranasal administration has been reported to be a potential pathway for nose-to-brain delivery of therapeutic agents that circumvents the blood-brain ...

A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing (Neo)adjuvant Therapies

Surgery is often the first treatment for many solid tumors. However, local relapses frequently occur following primary tumor resection, despite adjuvant or neo-adjuvant therapies. This occurs when surgical margins are insufficiently tumor-free, resulting in residual cancer cells. From a biological and immunological perspective, surgery is not a null event; the wound healing environment is known to induce both pro- and anti-tumorigenic pathways. As a consequence, preclinical models for drug development aimed at preventing local relapse should incorporate surgical resection when testing new (neo)adjuvant therapies, to model the clinical settings in patients treated with surgery.
Here, we describe a mouse model of incomplete surgical resection of WEHI 164 soft tissue sarcoma that allows testing of (neo)adjuvant therapies in the setting of a wound healing response. In this model, 50% or 75% of the tumor is removed, leaving behind some cancer tissue in situ to model gross residual disease after surgery in the clinical setting. This model allows testing therapies in the context of surgery while also considering the wound healing response, which may affect the efficacy of (neo)adjuvant treatments. The incomplete surgical resection results in reproducible regrowth of the tumor in all mice in the absence of adjuvant therapy. Adjuvant treatment with checkpoint blockade results in reduced tumor regrowth. This model is thus appropriate for testing therapies in the context of debulking surgery and its associated wound healing response and can be extended to other types of solid cancer.

A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing Neoadjuvant Therapies

In this protocol, we describe a mouse model of incomplete surgical resection of soft tissue sarcoma for testing (neo)adjuvant therapies.

시험을 위해 불완전하게 절제술된 연조직 육종의 마우스 모델(Neo) 보조 요법

Surgery is often the first treatment for many solid tumors. However, local relapses frequently occur following primary tumor resection, despite adjuvant ...

Functional Assessment of the Donor Heart During Ex Situ Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography

Heart transplantation remains the gold standard treatment for advanced heart failure. However, the current critical organ shortage has resulted in the allocation of a growing number of donor hearts with extended criteria. These marginal grafts are associated with a high risk of primary graft failure and may benefit from ex situ perfusion before transplant. This technology allows for extended organ preservation using warm oxygenated blood perfusion with continuous metabolic monitoring. The only NESP device currently available for clinical practice perfuses the organ in an unloaded non-working state, which does not allow for functional assessment of the beating heart. We therefore developed an original platform of NESP in working mode conditions with adjustment of left ventricular preload and afterload. This protocol was applied in porcine hearts. Ex situ functional assessment of the heart was achieved with intracardiac conductance catheterization and surface echocardiography. Along with a description of the experimental protocol, we herein report the main results, as well as pearls and pitfalls associated with the acquisition of pressure-volume loops and myocardial power during NESP. Correlations between hemodynamic findings and ultrasound variables are of major interest, especially for further rehabilitation of donor hearts before transplantation. This protocol aims to improve the assessment of donor hearts to both increase the donor pool and reduce the incidence of primary graft failure.

Functional Assessment of the Donor Heart During Ex Situ Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography

A reliable noninvasive approach for functional assessment of the donor heart during normothermic ex situ heart perfusion (NESP) is lacking. We herein describe a protocol for ex situ assessment of myocardial performance using the epicardial echocardiography and conductance catheter method.

현장 관류 중 기증자 심장의 기능 평가: 압력-부피 루프 및 표면 심초음파의 통찰력

Heart transplantation remains the gold standard treatment for advanced heart failure. However, the current critical organ shortage has resulted in the ...

Partial Sciatic Nerve Ligation: A Mouse Model of Chronic Neuropathic Pain to Study the Antinociceptive Effect of Novel Therapies

Management of chronic pain remains challenging to this day, and current treatments are associated with adverse effects, including tolerance and addiction. Chronic neuropathic pain results from lesions or diseases in the somatosensory system. To investigate potential therapies with reduced side effects, animal pain models are the gold standard in preclinical studies. Therefore, well-characterized and well-described models are crucial for the development and validation of innovative therapies. 
Partial ligation of the sciatic nerve (pSNL) is a procedure that induces chronic neuropathic pain in mice, characterized by mechanical and thermal hypersensitivity, ongoing pain, and changes in limb temperature, making this model a great fit to study neuropathic pain preclinically. pSNL is an advantageous model to study neuropathic pain as it reproduces many symptoms observed in humans with neuropathic pain. Furthermore, the surgical procedure is relatively fast and straightforward to perform. Unilateral pSNL of one limb allows for comparison between the ipsilateral and contralateral paws, as well as evaluation of central sensitization. 
To induce chronic neuropathic hypersensitivity, a 9-0 non-absorbable nylon thread is used to ligate the dorsal third of the sciatic nerve. This article describes the surgical procedure and characterizes the development of chronic neuropathic pain through multiple commonly used behavioral tests. As a plethora of innovative therapies are now being investigated to treat chronic pain, this article provides crucial concepts for standardization and an accurate description of surgeries required to induce neuropathic pain.

Partial sciatic nerve ligation induces long-lasting chronic neuropathic pain, characterized by exaggerated responses to thermal and mechanical stimuli. This mouse model of neuropathic pain is commonly used to study innovative therapies for pain management. This article describes in detail the surgical procedure to improve standardization and reproducibility.

부분 좌골 신경 결찰: 새로운 치료법의 항통각수용 효과를 연구하기 위한 만성 신경병성 통증의 마우스 모델

Management of chronic pain remains challenging to this day, and current treatments are associated with adverse effects, including tolerance and addiction. ...