Research on rat models of hypobaric hypoxia-induced pulmonary hypertension
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- 英文论文题名：Research on rat models of hypobaric hypoxia-induced pulmonary hypertension
- 论文作者：T.-T.MA ; Y WANG ; X.-L.ZHOU ; H.JIANG ; R.GUO ; L.-N.JIA ; H.CHANG ; Y GAO ; X.-Y.YAO ; Z.-M.GAO ; L.PAN
- 英文论文作者：T.-T.MA ; Y WANG ; X.-L.ZHOU ; H.JIANG ; R.GUO ; L.-N.JIA ; H.CHANG ; Y GAO ; X.-Y.YAO ; Z.-M.GAO ; L.PAN ; Department of Geriatric Medicine ; Beijing Shijitan Hospital ; Capital Medical University ; Department of Hypoxia Laboratory ; Beijing Shijitan Hospital ; Capital Medical University ; Department of Pathology ; Beijing Shijitan Hospital ; Capital Medical University ; Health Science Center of Peking University
- 年：2016
- 作者机构：Department of Geriatric Medicine,Beijing Shijitan Hospital,Capital Medical University;Department of Hypoxia Laboratory,Beijing Shijitan Hospital,Capital Medical University;Department of Pathology,Beijing Shijitan Hospital,Capital Medical University;Health Science Center of Peking University;
- 英文论文关键词：Hypobaric hypoxia ; Pulmonary hypertension ; Animal models
- 会议召开时间：2016-06-25
- 会议录名称：青藏铁路运营十周年学术研讨会卫生系统论文集
- 语种：英文
- 分类号：R-332;R544.1
- 学会代码：ZGTD
- 会议名称：青藏铁路运营十周年学术研讨会
- 会议地点：中国西藏拉萨
- 主办单位：中国铁道学会、青海省科学技术协会、西藏自治区科学技术协会
- 学会名称：中国铁道学会
- 页数：8
- 文件大小：3801k
- 原文格式：O
- 会议级别：全国
摘要
OBJECTIVE:Rat models of hypobaric hypoxia-induced pulmonary hypertension are commonly used in studies of chronic mountain sickness,while there are few researches specially focusing on these rats model.This study aims to exploring possible pathogenesis of hypobaric hypoxia-induced pulmonary hypertension by experimenting on hypobaric hypoxiainduced PH rat models at different simulate-altitudes.MATERIALS AND METHODS:32 healthy male SD rats were randomly divided into six groups of different degree and time period of hypobaric hypoxia.The mean pulmonary arterial pressure(m PAP),right ventricular pressure(RVSP),the right ventricle(RV),left ventricular(LV),ventricular septal(S),the right ventricular hypertrophy index(RVHI)[calculated under the formula of RV/(LV + S)],hematoxylin-eosin staining,elastic fibers staining,the ratio of the thickness of vascular wall to its outer diameter(MT%),the ratio of the cross-sectional area of the middle vascular wall to the total vascular cross-sectional area(MA%);the a-SMA,and the Ki6 expressions were detected to evaluated the pulmonary hypertension.RESULTS:There were significant differences of the mPAP,RVSP and RVHI value between the hypobaric hypoxia groups and the control group(p < 0.05).The mPAP,RVSP,RVHI,MT%,MA%,α-SMA,and Ki6 of rats in model groups at an altitude of 3KM were higher than those of the control group,which raised gradually with the number of weeks increasing.The mPAP,RVSP,RV/(LV + S) value,MT%,MA%,a-SMA,and Ki67 of the 5KM-4W group were significantly higher than those of the control group(p < 0.05).CONCLUSIONS:Rat models with pulmonary hypertension at different altitudes have been successfully established by automatic adjusting hypobaric hypoxia chamber.Exposure to a low oxygen environment at a simulate-altitude of 3km for 8 weeks have caused the pathological remodeling of pulmonary vascular walls and pulmonary hypertension,and further led to a series of pathological changes,including right ventricular hypertrophy.This model is easy to be replicated with good reproducibility and provides evidence for clinical trial of drugs.
OBJECTIVE:Rat models of hypobaric hypoxia-induced pulmonary hypertension are commonly used in studies of chronic mountain sickness,while there are few researches specially focusing on these rats model.This study aims to exploring possible pathogenesis of hypobaric hypoxia-induced pulmonary hypertension by experimenting on hypobaric hypoxiainduced PH rat models at different simulate-altitudes.MATERIALS AND METHODS:32 healthy male SD rats were randomly divided into six groups of different degree and time period of hypobaric hypoxia.The mean pulmonary arterial pressure(m PAP),right ventricular pressure(RVSP),the right ventricle(RV),left ventricular(LV),ventricular septal(S),the right ventricular hypertrophy index(RVHI)[calculated under the formula of RV/(LV + S)],hematoxylin-eosin staining,elastic fibers staining,the ratio of the thickness of vascular wall to its outer diameter(MT%),the ratio of the cross-sectional area of the middle vascular wall to the total vascular cross-sectional area(MA%);the a-SMA,and the Ki6 expressions were detected to evaluated the pulmonary hypertension.RESULTS:There were significant differences of the mPAP,RVSP and RVHI value between the hypobaric hypoxia groups and the control group(p < 0.05).The mPAP,RVSP,RVHI,MT%,MA%,α-SMA,and Ki6 of rats in model groups at an altitude of 3KM were higher than those of the control group,which raised gradually with the number of weeks increasing.The mPAP,RVSP,RV/(LV + S) value,MT%,MA%,a-SMA,and Ki67 of the 5KM-4W group were significantly higher than those of the control group(p < 0.05).CONCLUSIONS:Rat models with pulmonary hypertension at different altitudes have been successfully established by automatic adjusting hypobaric hypoxia chamber.Exposure to a low oxygen environment at a simulate-altitude of 3km for 8 weeks have caused the pathological remodeling of pulmonary vascular walls and pulmonary hypertension,and further led to a series of pathological changes,including right ventricular hypertrophy.This model is easy to be replicated with good reproducibility and provides evidence for clinical trial of drugs.
OBJECTIVE:Rat models of hypobaric hypoxia-induced pulmonary hypertension are commonly used in studies of chronic mountain sickness,while there are few researches specially focusing on these rats model.This study aims to exploring possible pathogenesis of hypobaric hypoxia-induced pulmonary hypertension by experimenting on hypobaric hypoxiainduced PH rat models at different simulate-altitudes.MATERIALS AND METHODS:32 healthy male SD rats were randomly divided into six groups of different degree and time period of hypobaric hypoxia.The mean pulmonary arterial pressure(m PAP),right ventricular pressure(RVSP),the right ventricle(RV),left ventricular(LV),ventricular septal(S),the right ventricular hypertrophy index(RVHI)[calculated under the formula of RV/(LV + S)],hematoxylin-eosin staining,elastic fibers staining,the ratio of the thickness of vascular wall to its outer diameter(MT%),the ratio of the cross-sectional area of the middle vascular wall to the total vascular cross-sectional area(MA%);the a-SMA,and the Ki6 expressions were detected to evaluated the pulmonary hypertension.RESULTS:There were significant differences of the mPAP,RVSP and RVHI value between the hypobaric hypoxia groups and the control group(p < 0.05).The mPAP,RVSP,RVHI,MT%,MA%,α-SMA,and Ki6 of rats in model groups at an altitude of 3KM were higher than those of the control group,which raised gradually with the number of weeks increasing.The mPAP,RVSP,RV/(LV + S) value,MT%,MA%,a-SMA,and Ki67 of the 5KM-4W group were significantly higher than those of the control group(p < 0.05).CONCLUSIONS:Rat models with pulmonary hypertension at different altitudes have been successfully established by automatic adjusting hypobaric hypoxia chamber.Exposure to a low oxygen environment at a simulate-altitude of 3km for 8 weeks have caused the pathological remodeling of pulmonary vascular walls and pulmonary hypertension,and further led to a series of pathological changes,including right ventricular hypertrophy.This model is easy to be replicated with good reproducibility and provides evidence for clinical trial of drugs.
引文
1)RAIESDANA A,LOSCALZO J.Pulmonary arterial hypertension.Ann Med 2006;38:95-110.
2)PAUUN R,MICHELAKIS ED.The metabolic theory of pulmonary arterial hypertension.Circ Res 2014;115:148-164.
3)DAVIES RJ,MORRELL NW.Molecular mechanisms of pulmonary arterial hypertension:role of mutations in the bone morphogenetic protein typeⅡreceptor.Chest 2008;134:1271-1277.
4)TASK FORCE FOR D.TREATMENT OF PULMONARY HYPERTENSION OF EUROPEAN SOCIETY OF C,EUROPEAN RESPIRATORY S,INTERNATIONAL SOCIETY OF H,LUNG T.GALIE N,HOEPER MM,HUMBERT M,TORBICKI A.VACHIERY JL.BARBERA JA,BEGHETTI M,CORRIS P.GAINE S,GIBBS JS,GOMEZ-SANCHFZ MA,JONDEAU G,KLEPEIKO W.OPITZ C,PEACOCK A.RUBIN L ZELLWEGER M,SIMONNEAU G.Guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Respir J 2009;34:1219-1263.
5)XU XQ,JING ZC High-altitude pulmonary hypertension.Eur Respir Rev 2009;18:13-17.
6)MAGGIORINI M,LEON-VELARDE F.High-altitude pulmonary hypertension:a pathophysiological entity to different diseases.Eur Respir J 2003;22:1019-1025.
7)DOGANCI S,YILDIRIM V,YESILDAL F EROL G,KADAN M,OZKAN G,AVCU F,OZGURTAS T.Comparison of angiogenic and proliferative effects of three commonly used agents for pulmonary artery hypertension(sildenafil,iloprost,bosentan):is angiogenesis always beneficial?Eur Rev Med Pharmacol Sci 2015;19:1900-1906.
8)STENMARK KR,FAGAN KA,FRID MG.Hypoxia-induced pulmonary vascular remodeling:cellular and molecular mechanisms.Circ Res 2006;99:675-691.
9)BALL MK,WAYPA GB,MUNGAI PT,NELSEN JM,CZECH L,DUDLEY VJ,BEUSSINK L DETTMAN RW,BERKELHAMER SK,STEINHORN RH,SHAH SJ,SCHUMACKER PT,Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1alpha.Am J Respir Crit Care Med 2014;189:314-324.
10)RABINOVITCH M.Molecular pathogenesis of pulmonary arterial hypertension.J Clin Invest 2008;118:2372-2379.
11)ZHAO LJ,HUANG SM,LIANGT,TANG.Pulmonary hypertension and right ventricular dysfunction in hemodialysis patients.Eur Rev Med Pharmacol Sci 2014;18:3267-3273.
12)MAIGNAN M,RIVERA-CH M,PRIVAT C.LEON-VELARDE F,RICHALET JP,PHAM I.Pulmonary pressure and cardiac function in chronic mountain sickness patients.Chest 2009;135:499-504.
13 KADYRALIEV TK.[The morphological changes in the pulmonary resistive vessels in the development of high-altitude pulmonary arterial hypertension],Arkh Patol 1990;52:36-40.
14)SCHERMULY RT,GHOFRANI HA,WILKINS MR,GRIMMINGER F.Mechanisms of disease:pulmonary arterial hypertension.Nat Rev Cardiol 2011;8:443-455.
15)BOSC LV,RESTA T,WALKER B,KANAGY NL Mechanisms of intermittent hypoxia induced hypertension.J Cell Mol Med 2010;14:3-17.
16)MACHADO RD.The molecular genetics and cellular mechanisms underlying pulmonary arterial hypertension.Scientifica(Cairo)2012;2012:106576.
17)GOMEZ-ARROYO J,SALEEM SJ,MIZUNO S,SYED AA,BOGAARD HJ,ABBATE A.TARASEVICIENE-STEWART.L,SUNG Y KRASKAUSKAS D,FARKAS D,CONRAD DH,NICOLLS MR,VOELKEL NF.A brief overview of mouse models of pulmonary arterial hypertension:problems and prospects.Am J Physiol Lung Cell Mol Physiol2012;302:L977-991.
18)GUIHAIRE J,HADDAD F,NOLY PE,BOULATE D,DECANTE B,DARTEVELLE P,HUMBERT M,VERHOYE JP,MERCIER O,FADEL E.Right ventricular reserve in a piglet model of chronic pulmonary hypertension.Eur Respir J2015;45:709-717.
19)MAARMAN G,LECOUR S,BUTROUS G,THIENEMANN F,SLIWA K.A comprehensive review:the evolution of animal models in pulmonary hypertension research;are we there yet?Pulm Circ 2013;3:739-756.
20)TEMPLE IP,MONFREDI O.QUIGLEY G,SCHNEIDER H,ZI M,CARTWRIGHT EJ.BOYETT MR,MAHADEVAN MS.HART G.Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model.Int J Cardiol 2014;177:423-428.
2)PAUUN R,MICHELAKIS ED.The metabolic theory of pulmonary arterial hypertension.Circ Res 2014;115:148-164.
3)DAVIES RJ,MORRELL NW.Molecular mechanisms of pulmonary arterial hypertension:role of mutations in the bone morphogenetic protein typeⅡreceptor.Chest 2008;134:1271-1277.
4)TASK FORCE FOR D.TREATMENT OF PULMONARY HYPERTENSION OF EUROPEAN SOCIETY OF C,EUROPEAN RESPIRATORY S,INTERNATIONAL SOCIETY OF H,LUNG T.GALIE N,HOEPER MM,HUMBERT M,TORBICKI A.VACHIERY JL.BARBERA JA,BEGHETTI M,CORRIS P.GAINE S,GIBBS JS,GOMEZ-SANCHFZ MA,JONDEAU G,KLEPEIKO W.OPITZ C,PEACOCK A.RUBIN L ZELLWEGER M,SIMONNEAU G.Guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Respir J 2009;34:1219-1263.
5)XU XQ,JING ZC High-altitude pulmonary hypertension.Eur Respir Rev 2009;18:13-17.
6)MAGGIORINI M,LEON-VELARDE F.High-altitude pulmonary hypertension:a pathophysiological entity to different diseases.Eur Respir J 2003;22:1019-1025.
7)DOGANCI S,YILDIRIM V,YESILDAL F EROL G,KADAN M,OZKAN G,AVCU F,OZGURTAS T.Comparison of angiogenic and proliferative effects of three commonly used agents for pulmonary artery hypertension(sildenafil,iloprost,bosentan):is angiogenesis always beneficial?Eur Rev Med Pharmacol Sci 2015;19:1900-1906.
8)STENMARK KR,FAGAN KA,FRID MG.Hypoxia-induced pulmonary vascular remodeling:cellular and molecular mechanisms.Circ Res 2006;99:675-691.
9)BALL MK,WAYPA GB,MUNGAI PT,NELSEN JM,CZECH L,DUDLEY VJ,BEUSSINK L DETTMAN RW,BERKELHAMER SK,STEINHORN RH,SHAH SJ,SCHUMACKER PT,Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1alpha.Am J Respir Crit Care Med 2014;189:314-324.
10)RABINOVITCH M.Molecular pathogenesis of pulmonary arterial hypertension.J Clin Invest 2008;118:2372-2379.
11)ZHAO LJ,HUANG SM,LIANGT,TANG.Pulmonary hypertension and right ventricular dysfunction in hemodialysis patients.Eur Rev Med Pharmacol Sci 2014;18:3267-3273.
12)MAIGNAN M,RIVERA-CH M,PRIVAT C.LEON-VELARDE F,RICHALET JP,PHAM I.Pulmonary pressure and cardiac function in chronic mountain sickness patients.Chest 2009;135:499-504.
13 KADYRALIEV TK.[The morphological changes in the pulmonary resistive vessels in the development of high-altitude pulmonary arterial hypertension],Arkh Patol 1990;52:36-40.
14)SCHERMULY RT,GHOFRANI HA,WILKINS MR,GRIMMINGER F.Mechanisms of disease:pulmonary arterial hypertension.Nat Rev Cardiol 2011;8:443-455.
15)BOSC LV,RESTA T,WALKER B,KANAGY NL Mechanisms of intermittent hypoxia induced hypertension.J Cell Mol Med 2010;14:3-17.
16)MACHADO RD.The molecular genetics and cellular mechanisms underlying pulmonary arterial hypertension.Scientifica(Cairo)2012;2012:106576.
17)GOMEZ-ARROYO J,SALEEM SJ,MIZUNO S,SYED AA,BOGAARD HJ,ABBATE A.TARASEVICIENE-STEWART.L,SUNG Y KRASKAUSKAS D,FARKAS D,CONRAD DH,NICOLLS MR,VOELKEL NF.A brief overview of mouse models of pulmonary arterial hypertension:problems and prospects.Am J Physiol Lung Cell Mol Physiol2012;302:L977-991.
18)GUIHAIRE J,HADDAD F,NOLY PE,BOULATE D,DECANTE B,DARTEVELLE P,HUMBERT M,VERHOYE JP,MERCIER O,FADEL E.Right ventricular reserve in a piglet model of chronic pulmonary hypertension.Eur Respir J2015;45:709-717.
19)MAARMAN G,LECOUR S,BUTROUS G,THIENEMANN F,SLIWA K.A comprehensive review:the evolution of animal models in pulmonary hypertension research;are we there yet?Pulm Circ 2013;3:739-756.
20)TEMPLE IP,MONFREDI O.QUIGLEY G,SCHNEIDER H,ZI M,CARTWRIGHT EJ.BOYETT MR,MAHADEVAN MS.HART G.Macitentan treatment retards the progression of established pulmonary arterial hypertension in an animal model.Int J Cardiol 2014;177:423-428.