间歇光照、呋喃苯胺酸、维生素C对肉鸡PHS的预防及其机理研究
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摘要
尽管国内外已对肉鸡肺动脉高压综合征(pulmonary hypertension syndrome，PHS)又称肉鸡腹水综合征(ascites)进行了多年研究，但它仍然是使世界养禽业遭受重大经济损失的一个疾病。全世界每年约有4％的肉鸡死于PHS，造成高达10亿美元的损失。
由于肉鸡PHS是一个多因性疾病，药物防治有局限性并且存在残留的问题。早期限饲可以降低PHS发病率，但会引起应激。控制光照能降低肉鸡PHS发病率和应激，并且方便、省电，但公认效果显著的1小时明：3小时暗的措施在国内难以执行和推广。寻求一种易行的控光措施更具有实际意义。由于对控制光照防治肉鸡PHS的机理尚不完全明了，方案的选择存在很大盲目性，因此，首先要清楚控制光照防治PHS的作用机制。
关于控制光照防治肉鸡PHS的报道主要是观察对生产性能和PHS发病率的影响，而对其机理仅从缺氧状况、红细胞比容、血液中甲状腺素、生长激素和糖皮质激素方面进行了研究。肺血管重构导致肺动脉高压(pulmonary hypertension，PH)持续发展并难以逆转，是哺乳动物PH的重要病理基础。PHS肉鸡也发生了肺动脉重构，但是其在肉鸡PHS的发生过程中是否占据与哺乳动物肺血管重构同等重要的地位，机制如何?控制光照降低PHS发病率的作用机理是否与肺血管形态改变有关，尚不清楚。因此，本文从氧自由基、血小板源生长因子-β受体(PDGF-βR)、蛋白激酶C-α(PKCα)及增殖细胞核抗原(PCNA)等变化入手，在体内和体外两个层次上探讨间歇光照对肉鸡肺血管重构的影响及其分子生物学机制，为指导生产实践提供理论依据。
试验Ⅰ间歇光照对肉鸡肺动脉高压综合征发病率及肺血管重构的影响。观察在低温环境下间歇光照对肉鸡PHS的防治效果及其对肉鸡肺血管重构的影响。320羽肉鸡随机分为4组：常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。记录PHS发病数、体重和耗料量，测定肺动脉的管壁面积与血管总面积之比(WA／TA)、平均中膜厚度(mMTPA)等指标。结果环境低温使PHS发病率升高，反映血管重构指标的WA／TA和mMTPA值也显著升高，而间歇光照能够有效地降低寒冷诱发的PHS发病率和上述各项值。控制光照期间间歇光照组肉鸡体重低于低温对照组，但最终体重和料重比与之无显著差异。在肉鸡生长早期实施间歇光照制度能够有效降低低温诱发的PHS发病率，抑制肺小动脉重构可能是其重要机理之一。
试验Ⅱ间歇光照对肉鸡肺动脉高压综合征发病率及体内脂质过氧化作用和抗氧化酶活性的影响。观察控制光照对低温诱导的肉鸡PHS发病率及体内脂质过氧化作用和抗氧化酶活性的影响。320羽肉鸡随机分为四个组。常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。低温显著升高了PHS发病率、右心全心比(RV／TV)、肺厚壁末稍血管百分率(TWPV％)和丙二醛(MDA)，而使血浆超氧化物歧化酶(SOD)活性降低。控制光照使SOD活性升高而显著降低了PHS发病率、RV／TV、TWPV％和MDA。减轻体内脂质过氧化作用，提高机体抗氧化酶的活性和减轻以非肌型肺动脉肌型化为特征肺血管重构，可能是间歇光照降低肉鸡PHS发病率的部分机制。
试验Ⅲ间歇光照对低温诱导的肉鸡肺细小动脉血管重构及其PKCα表达的影响。观察在低温环境下间歇光照对肉鸡肺细小动脉蛋白激酶Cα(PKCα)表达的影响及其与肺血管重构的关系。320羽肉鸡随机分为四个组。常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。测定RV／TV、MDA、SOD、WA／TA、mMTPA、红细胞压积(PCV)；采用免疫组化方法标记肺动脉PKCα，以OD值代表PKCα的表达。结果环境低温使肉鸡PHS发病率升高，RV／TV、WA／TA、mMTPA、MDA值和肺细小动脉PKCα的OD值显著升高，而间歇光照能够有效地降低寒冷诱发的PHS发病率和上述指标。肺小动脉PKCα的表达从23日龄起与mMTPA和WA／TA呈正相关，并且具有显著性。寒冷诱使肉鸡肺小动脉PKCα表达的上调可能参与了肺血管重构的形成过程，间歇光照抑制肺血管重构可能与PKCα下调有关。
试验Ⅳ间歇光照对低温诱导的肉鸡肺细小动脉血管重构及其PDGF-β受体表达的影响。观察在低温环境下间歇光照对肉鸡肺细小动脉PDGF-β受体表达的影响，及其与肺血管重构的关系。320羽肉鸡随机分为四个组，常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。测定PCV、WA／TA和mMTPA等指标；采用免疫组化方法标记肺动脉PDGF-β受体，以OD值代表PDGF-β受体的表达。结果环境低温使PDGF-β受体表达上调，WA／TA和mMTPA值也显著升高，而间歇光照明显抑制血管重构，并且使肺动脉PDGF-D受体的OD值降低。PDGF-β受体的表达从23日龄开始与mMTPA和WA／TA呈正相关，并且具有显著性。PDGF-β受体表达上调可能与低温所致肺小动脉重构有密切关系，而间歇光照减轻肉鸡肺血管重构可能与抑制PDGF-β受体表达有关。
试验Ⅴ间歇光照对低温诱导的肉鸡肺细小动脉血管重构及其PCNA表达的影响。观察在低温环境下间歇光照对肉鸡肺细小动脉增殖细胞核抗原(PCNA)表达的影响，并探讨PCNA与肺血管重构的关系。320羽肉鸡随机分为四个组，常温组按常规饲养；低温三个组采用低温诱发PHS，并于9 d～30 d分别在夜间停止光照0、3、5 h，以后恢复连续光照。测定WA／TA和mMTPA等指标；采用免疫组化方法标记PCNA，图像分析软件分别计数每条血管中膜PCNA阳性细胞数和细胞总数，求出百分数即为增殖指数(PI)。结果环境低温使肺动脉的WA／TA和mMTPA值和PCNA值显著升高，而间歇光照能够有效地减轻寒冷诱发的肺动脉重构和PCNA值。在肉鸡快速生长的早期采用间歇光照能够抑制寒冷所致的肺血管重构可能与抑制肺动脉平滑肌细胞增殖有关。
试验Ⅵ添加呋喃苯胺酸对低温诱导的肉鸡肺动脉高压综合征的发病率及肺血管重构的影响。观察在低温环境下呋喃苯胺酸对肉鸡PHS的防治效果及其对肺血管重构的影响。240羽肉鸡于14 d时随机分为A、B和C三组分置于两个鸡舍。A组按常规饲养，B组和C组采取低温诱发PHS，并从30 d至44 d B组不添加药物而C组于日粮中添加0.015％的呋喃苯胺酸。记录每周PHS发病数、体重。定期测定RV／TV、PCV、WA／TA和mMTPA等各项值。结果饲料中添加呋喃苯胺酸降低了寒冷诱发的PHS发病率。B组RV／TV、WA／TA和mMTPA值显著升高，而C组使之降低，并在44 d差异显著；C组体重显著低于B组。降低肺动脉压，抑制以肺动脉壁肥厚为特征的血管重构可能是呋喃苯胺酸有效降低低温所致PHS发病率的部分机制。
试验Ⅶ维生素C对常温下肉鸡肺动脉高压综合征发病率及肺血管重构的影响。观察在常温环境下维生素C对肉鸡PHS的防治效果及其对肺血管重构的影响。150羽肉鸡于21 d时随机分为C、T1和T2组，按常规饲养，C组不添加药物，T1组和T2组分别从21 d至37 d在饲料中添加维生素C 200 mg／kg和500 mg／kg。统计PHS的死亡数并定期称重。测定RV／TV、PCV、MDA、SOD、WA／TA和mMTPA等指标。结果与对照组相比，T1组PHS死亡率和RV／TV值显著降低，80-200微米肺动脉WA／TA和mMTPA值显著降低，PCV和MDA值极显著降低。T2组PHS死亡率与对照组相同，PCV值显著降低，50-80微米肺动脉的WA／TA和mMTPA值极显著高于对照组，MDA水平极显著高于对照组而SOD值显著降低。降低PCV值、清除体内过多的氧自由基及减轻肺血管重构可能是低剂量维生素C有效防治PHS的部分机制，而使氧自由基产生增多，导致肺血管重构可能是高剂量VC防治PHS失败的部分原因
试验Ⅷ蛋白激酶C抑制剂Calphostin C对PDGF-BB诱导的肉鸡肺动脉血管平滑肌细胞增殖的影响．探讨蛋白激酶C抑制剂Calphostin C对血小板源生长因子(PDGF-BB)诱导的肉鸡肺动脉平滑肌细胞(PASMC)增殖的影响。肉鸡肺动脉平滑肌细胞体外培养，用PDGF-BB刺激PASMC，采用细胞记数法和流式细胞仪测定Calphostin C对PASMC增殖的影响．结果Calphostin C显著地抑制PDGF-BB诱使的PASMC增殖，使细胞生长停滞于G_0／G_1期。蛋白激酶C抑制剂Calphostin C抑制了PASMC增殖，提示PDGF-BB刺激血管平滑肌细胞增殖与PKC信号传导通道有关，Calphostin C可能作为防治肺血管重构的一种药物。
试验ⅨX／X0体系作用的肺动脉内皮细胞条件培养液对内鸡肺动脉平滑肌细胞的促增殖作用及褪黑激素对其的影响。观察黄嘌呤-黄嘌呤氧化酶(xanthine-xanthineoxidase，X-XO)条件培养液对肉鸡肺血管平滑肌细胞是否有促增殖作用，及褪黑激素能否抑制其增殖。肉鸡肺动脉平滑肌细胞与X／XO内皮细胞条件培养液共培养刺激PASMC，采用流式细胞仪测定X／XO条件培养液和褪黑激素对PASMC增殖的影响，并检测培养液中的丙二醛(MDA)含量。与正常内皮细胞条件培养基相比，X／XO条件培养基促使PASMC发生增殖，并从G_0／G_1期进入S和G_2／M期，其培养液中MDA含量显著高于对照组；当预先加入褪黑激素时，抑制了X／XO条件培养液的促平滑肌细胞增殖作用，G_0／G_1期细胞比例提高，而S期、G_2／M期细胞减少。褪黑激素组细胞培养液中MDA含量显著低于X／XO模型组。清除培养液中的氧自由基可能是褪黑激素抑制X／XO条件培养液诱导肉鸡肺动脉平滑肌细胞增殖的机制之一。
Despite investigation of the syndrome for many years, ascites or pulmonary hypertension syndrome (PHS) is still a condition that inflicts financial loss on poultry farmers around the world. Approximately 4% of all broilers die from PHS, amounting to a loss estimated at $1 billion annually. So, prevention and cure of PHS are especially important. There are multiple aetiologies of pulmonary hypertension syndrome(PHS). The main cause of which is rapid growth. Thus every drug has its limit to cure the disease. Remanet of drug in meat also is a problem. Early feed restriction could slow broiler growth at early age, reduce ascites incidence, but could induce stress too. Lighting restriction at early age could decrease ascites incidence and stress effectively.
1 light (L):3dark (D) lighting program is recognized as best schedule to prevent ascites, but is difficult to apply in China. To implore a simple and effective lighting schedule would be of benefit to prevent ascites. Since the mechanism of Lighting restriction remain unclear, The choose of lighting schedules are difficult.
In recent years, most ascites research has centred on production capability and ascites incidence of broilers. The investigations on the aetiology of ascites in chickens include oxygen level, thyroxin, growth hormone and cortin. Pulmonary vascular remodeling is an important pathological feature of hypoxia pulmonary hypertension in mammal, leading to increased pulmonary vascular resistance and reduced compliance. Since vascular remodeling becomes progressively more important as the disease advances, an possibly more fruitful approach may be to target pulmonary vascular remodeling. It has been fould that Pulmonary vascular remodeling also occurred in PHS in broilers. It's mechanism remain unclear. The present study was conducted to evaluate the association of changes of protein kinase Ca (PKCa), platelet-derived growth factor BB(PDGF-BB) and its receptor (PDGF-βreceptor)、proliferating cell nuclear antigen (PCNA) and oxygen free radical(OFR) with alterations in pulmonary vascular structure for understanding the pathogenesis of pulmonary vascular remodeling in vito and in vitro, to implore the effect of intermittent lighting schedule、furosemide and vitamin C on pulmonary vascular remodeling respectively. If PKC-a and PDGF actually play a critical role in pulmonary vascular remodeling. Both of them may be to target pulmonary vascular remodeling.
Test 1 Effects of intermittent lighting schedules on incidence of pulmonary hypertension syndrome and pulmonary vascular remodeling in broilers.The purpose of the present study was to examine the efficacy of imposing intermittent lighting schedules on reduction of the incidence of ascites(or Pulmonary Hypertension Syndrome,PHS)induced by cool ambient temperature and to investigate its effect on the pulmonary vascular remodeling of broiler chickens. A total of three hundred and twenty broilers were randomly allocated to four rooms at 9 days of age. In one room, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L: 0D and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce PHS. PHS cases, body weights and feed intake were measured weekly for each group. The ratio of vessel wall area to total area (WA/TA) and mean medial thickness in pulmonary arterioles (mMTPA) were determined . The results indicated that the cool ambient temperature could increase morbidity of PHS in broilers, the values of WA/TA and mMTPA also were increased significantly, whereas the IL schedule could successfully decrease the morbidity of PHS and the values of WA/TA and mMTPA. Birds in IL groups were lighter than that in LC group during light restriction period, but both the final body weights and total feed conversion ratio were not significantly affected by the lighting program in all birds subjected to low temperature. It is concluded that introduction of IL schedules during the early growing period is of benefit to reduce PHS morbidity induced by cool ambient temperature in fast-growing broilers, and attenuated pulmonary vascular remodeling may be involved in the underlying mechanisms.
Test 2 Effects of intermittent lighting schedules on the incidence of ascites, the lipid peroxidation and enzymatic antioxidant activity of broilers. The purpose of the present study was to examine the efficacy of intermittent lighting schedules at night in reducing the incidence of ascites induced by cool environment and to test its effect on the lipid peroxidation and activity of enzymatic antioxidant in broilers. A total of three hundred and twenty broilers were randomly aUocated to four rooms at 9 days of age. In one Toom, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L:0D and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce pulmonary hypertension syndrome(PHS). The results showed that Low temperature significantly increased RV/TV and the ascites morbidity, so were the plasma MDA concentration and the percentages of TWPV. Whereas the plasma SOD activity was decreased. The intermittent lighting (IL) schedules had successfully reduced PHS in broilers. The values of RV/TV, plasma MDA concentration and the percentages of TWPV were reduced significantly, whereas the activity of the plasma SOD were significantly promoted. Body weights (BW) were reduced significantly by light restriction at 20 days of age. However, IL broilers exhibited compensatory growth during the finisher period in such a way that at Day 44, a similar BW as that of their CL counterparts was attained. The results indicated that alleviated the lipid peroxidation, enhanced the enzymatic antioxidant activity and reduced the percentages of the TWPA may be the part mechanism of intermittent lighting (IL) schedule reduced ascites of broiler.
Test 3 Effects of intermittent lighting schedules on expression of PKCa in pulmonary arterioles and its association with pulmonary vascular remodeling in broilers induced by cold temperature. The purpose of the present study was to examine the effects of intermittent lighting schedules on expression of protein kinase C a (PKC a) in pulmonary arterioles in broilers exposed to cold temperature and its relationship with pulmonary vascular remodeling. A total of three hundred and twenty broilers were randomly allocated to four rooms at 9 days of age. In one room, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L: OD and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce pulmonary hypertension syndrome(PHS). PHS incidence was recorded. Malonilaldehyde (MDA) concentration,packed cell volume (PCV), Mean medial thickness (mMTPA), Ratio of vessel wall area to total area (WA/TA) and right to total ventricle (RV/TV) were determined. The expression of PKCa in the pulmonary arterioles labeled by immunohistochemistry and quantified by measuring optical density (OD). The results indicated that the cool ambient temperature could increase morbidity of PHS in broilers. The value of MDA, WA/TA and mMTPA were increased significantly, the same as the OD value of PKCa, whereas the IL schedules could successfully decrease the morbidity of PHS .The value of WA/TA ,mMTPA, MDA and PKCa were decreased too. It was concluded that cold exposure enhanced arterioles PKCa expression, which might involved in the underlying mechanisms of pulmonary vascular remodeling. The introduction of IL schedules were of benefit to attenuate pulmonary vascular remodeling ,which may be correlated with the decrease of PKC a expression.
Test 4 Effects of intermittent lighting schedules on expression of PDGF-βreceptor in pulmonary arterioles and its association with pulmonary vascular remodeling in broilers induced by cold ambient temperature. The purpose of the present study was to examine the effects of intermittent lighting schedules on expression of platelet-derived growth factorβreceptor (PDGF-βreceptor) in pulmonary arterioles in broilers exposed to cold temperature and its relationship with pulmonary vascular remodeling. A total of three hundred and twenty broilers were randomly allocated to four rooms. In one room, the continuous lighting schedule (CL) of 24 L: 0D was maintained, ambient temperature kept normal (group NC),while in other three rooms ,the chickens were subjected to cool ambient temperature to induce PHS. The continuous lighting schedule of 24 L:0D (group LC) and the intermittent lighting (IL) schedule of 21 L:3 D(group L1) and 19 L:5 D (group L2) were imposed respectively from 9 to 30 days of age. PHS incidence was recorded. Mean medial thickness (mMTPA), ratio of vessel wall area to total area (WA/TA) in pulmonary arterioles ,ratio of right to total ventricle (RV/TV), malonilaldehyde (MDA) concentration and packed cell volume (PCV) were determined respectively. The expression of PDGF-βreceptor in the pulmonary arterioles labeled by immunohistochemistry and quantified by measuring optical density (OD). The results indicated that the cool ambient temperature could increase the value of WA/TA and mMTPA in pulmonary arterioles, the same as the OD value of PDGF-βreceptor, whereas the intermittent lighting (IL) schedule could successfully decrease the value of WA/TA、mMTPA and PDGF-βreceptor. It was concluded that cold exposure enhanced PDGF-β receptor expression in pulmonary arterioles, which might involved in the underlying mechanisms of pulmonary vascular remodeling. The introduction of intermittent lighting schedules were of benefit to attenuate pulmonary vascular remodeling , which may be correlated with the decrease of PDGF-βreceptor expression in pulmonary arterioles.
Test 5 Effects of intermittent lighting schedules on expression of PCNA in pulmonary arterioles and its association with pulmonary vascular remodeling in broilers induced by cold temperature. The objection of the present study was to examine the effects of intermittent lighting schedules on expression of proliferating cell nuclear antigen (PCNA) in pulmonary arterioles in broilers exposed to cold temperature and its relationship with pulmonary vascular remodeling. A total of three hundred and twenty broilers were randomly allocated to four rooms at 9 days of age. In one room, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L: 0D and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce pulmonary hypertension syndrome(PHS). PHS incidence was recorded. The mean medial thickness (mMTPA), ratio of vessel wall area to total area (WA/TA) in pulmonary arterioles ,Ratio of right to total ventricle (RV/TV), packed cell volume (PCV) were determined. The expression of PCNA in the pulmonary arterioles labeled by immunohistochemistry and quantified by counting the number of the positive PCNA cells and total vascular smooth ceils using computer-image analytic software and then calculating the PCNA index (PI). The results indicated that the cool ambient temperature could increase the value of WA/TA and mMTPA significantly, the same as the PI, whereas the IL schedules could successfully attenuate pulmonary vascular remodeling and PI. It was concluded that introduction of intermittent lighting schedule during the early growing period was of benefit to attenuate pulmonary vascular remodeling induced by cool ambient temperature in fast-growing broilers, and the inhibition of vascular smooth cell proliferation might be involved in the underlying mechanisms.
Test 6 Effects of dietary furosemide on incidence of pulmonary hypertension syndrome and pulmonary vascular remodeling in broilers induced by cool environmental temperatures. The objective of the present study was to evaluate the influence of dietary furosemide (FURO) on the incidence of Pulmonary Hypertension Syndrome(PHS) induced by cool ambient temperature and to investigate its effect on the pulmonary vascular remodeling of broiler chickens. A total of two hundred and forty broilers were randomly allocated to three groups. The birds in group A were fed a grower diet and kept in normal ambient temperature from 14 to 44 day of age. Group C and group B were subjected to cool ambient temperature to induce PHS and were fed a grower diet with (group C) or without 0.015 percent furosemide (group B) from 30 to 44 day of age. PHS incidence, body weights were measured weekly for each group. Heart, Lung and blood samples were taken from 10 birds per group randomly selected at 14, 23, 30, 37 and 44 days of age, for the determination of the ratio of vessel wall area to total area (WA/TA), mean medial thickness in pulmonary arterioles (mMTPA), etc. It was found that birds exposed to cold had higher PHS morbidity. However, it was reduced by dietary furosemide supplementation. The value of right to total ventricular weight ratios (RV/TV) and packed red blood cell volume (PCV) in group B were significantly higher than that in group A, also were the value of WA/TA and mMTPA which served as describing pulmonary vessel remodeling. Birds fed 0.015 percent furosemide had significantly lower RV/TV, WA/TA and mMTPA than that in group B, also were body weights, whereas PCV were increased. It was concluded that dietary furosemide reduced morbidity of PHS induced by cool ambient temperature, presumably by reducing pulmonary arterial pressure. Attenuated pulmonary vascular remodeling might be involved in the underlying mechanisms too.
Test 7 Effects of dietary vitamin C on mortality of pulmonary hypertension syndrome and pulmonary vascular remodeling in broilers under normal environmental temperatures. The objective of the present study was to evaluate the influence of dietary vitamin C on the mortality of pulmonary hypertension syndrome(PHS) under normal ambient temperature and to investigate its effect on the pulmonary vascular remodeling of broiler chickens. A total of one hundred and fifty broilers were randomly allocated to three groups in one room, in which temperature kept normal. From 21 to 37d, the birds in control group (C) were fed a grower diet, treat 1 (T_1) and treat 2 group(T_2) were fed a grower diet with 200mg/kg and 500mg/kg respectively. PHS mortality and body weights were measured weekly for each group. Heart, Lung and blood samples were taken for the determination of SOD and MDA concentration in blood plasma, packed cell volume (PCV), mean medial thickness in pulmonary arterioles (mMTPA), and the ratio of vessel wall area to total area (WA/TA), right ventricle to total ventricular weight. It was found that birds fed 200mg/kg vitamin C had lower PHS mortality than that in group C. The value of WA/TA、mMTPA of pulmonary artery with outer diameter from 80 to 200μm and PCV vaule were significantly reduced, also were the MDA level, whereas SOD concentration were significantly increased. The birds fed 500mg/kg vitamin C had same PHS mortality as control group. The percentages of WA/TA and mMTPA of pulmonary artery with outer diameter from 50 to 80μm and the concentration of MDA were increased significantly, whereas PCV and SOD concentration were reduced. It was concluded that decreasing PCV value, weeding up extra oxygen free radical (OFR) and attenuating pulmonary artery remodeling might be involved in the underlying mechanisms of prevention PHS by low dose vitamin C, Whereas promoting OFR level and inducing pulmonary artery remodeling might be the cause of high dose vitamin C failing to prevent PHS.
Test 8 Effects of protein kinase C inhibitor-Calphostin C on proliferation induced by PDGF-BB in pulmonary artery smooth muscle cells of broilers. To xplore the effects of protein kinase C inhibitor-Calphostin C on proliferation in pulmonary artery smooth muscle cells (PASMC) of broilers induced by PDGF-BB. Pulmonary vascular smooth muscle cells were cultured in vitro and stimulated by PDGF-BB. The effects of Calphostin C on PASMC proliferation were analyzed by using flowcytomerty and cell counting. The PASMC proliferation induced by PDGF-BB was significantly inhibited by Calphostin C and the cells were stagnated on G_0/G_1 phase. The result of Calphostin C inhibition on the PASMC proliferation suggested that proliferation induced by PDGF-BB may be correlated with PKC pathway. Calphostin C may be an agent for prevention of vascular remodeling.
Test 9 Effects of melatonin on proliferation of pulmonary artery smooth muscle cells in broilers induced by xanthine-xanthine oxidase conditioned medium. To investigate the effects of X/XO conditioned medium on proliferation of pulmonary artery smooth muscle cells (PASMC) in broilers, and melatonin could or not attenuate PASMC proliferation induced by X/XO conditioned medium. Pulmonary artery smooth muscle cells were cultured in vitro with X/XO endothelial cells conditioned medium to induce proliferation of PASMC. The effect of melatonin on PASMC proliferation were analyzed using flowcytomerty. The MDA level in medium were detected. Compared to normal PAEC medium, X/XO conditioned medium lead to PASMC proliferation, stimulate PASMC from G_0/G_1 phase to S and G_2/M phase. The MDA level in PASMC cultured with X/XO conditioned medium were significantly higher than that in PASMC cultured with normal PAEC medium. The PASMC proliferation induced by X/XO conditioned medium was successfully inhibited by melatonin, which added in medium ahead, and the number of cells on G_0G_1 phase were higher, whereas on S and G_2/M phase lower. The MDA level in melatonin group was less than X/XO group. Eliminating of OFR may be involved in the underlying mechanisms of the melatonin on inhibiting proliferation of PASMC in broilers induced by X/XO conditioned medium.
由于肉鸡PHS是一个多因性疾病，药物防治有局限性并且存在残留的问题。早期限饲可以降低PHS发病率，但会引起应激。控制光照能降低肉鸡PHS发病率和应激，并且方便、省电，但公认效果显著的1小时明：3小时暗的措施在国内难以执行和推广。寻求一种易行的控光措施更具有实际意义。由于对控制光照防治肉鸡PHS的机理尚不完全明了，方案的选择存在很大盲目性，因此，首先要清楚控制光照防治PHS的作用机制。
关于控制光照防治肉鸡PHS的报道主要是观察对生产性能和PHS发病率的影响，而对其机理仅从缺氧状况、红细胞比容、血液中甲状腺素、生长激素和糖皮质激素方面进行了研究。肺血管重构导致肺动脉高压(pulmonary hypertension，PH)持续发展并难以逆转，是哺乳动物PH的重要病理基础。PHS肉鸡也发生了肺动脉重构，但是其在肉鸡PHS的发生过程中是否占据与哺乳动物肺血管重构同等重要的地位，机制如何?控制光照降低PHS发病率的作用机理是否与肺血管形态改变有关，尚不清楚。因此，本文从氧自由基、血小板源生长因子-β受体(PDGF-βR)、蛋白激酶C-α(PKCα)及增殖细胞核抗原(PCNA)等变化入手，在体内和体外两个层次上探讨间歇光照对肉鸡肺血管重构的影响及其分子生物学机制，为指导生产实践提供理论依据。
试验Ⅰ间歇光照对肉鸡肺动脉高压综合征发病率及肺血管重构的影响。观察在低温环境下间歇光照对肉鸡PHS的防治效果及其对肉鸡肺血管重构的影响。320羽肉鸡随机分为4组：常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。记录PHS发病数、体重和耗料量，测定肺动脉的管壁面积与血管总面积之比(WA／TA)、平均中膜厚度(mMTPA)等指标。结果环境低温使PHS发病率升高，反映血管重构指标的WA／TA和mMTPA值也显著升高，而间歇光照能够有效地降低寒冷诱发的PHS发病率和上述各项值。控制光照期间间歇光照组肉鸡体重低于低温对照组，但最终体重和料重比与之无显著差异。在肉鸡生长早期实施间歇光照制度能够有效降低低温诱发的PHS发病率，抑制肺小动脉重构可能是其重要机理之一。
试验Ⅱ间歇光照对肉鸡肺动脉高压综合征发病率及体内脂质过氧化作用和抗氧化酶活性的影响。观察控制光照对低温诱导的肉鸡PHS发病率及体内脂质过氧化作用和抗氧化酶活性的影响。320羽肉鸡随机分为四个组。常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。低温显著升高了PHS发病率、右心全心比(RV／TV)、肺厚壁末稍血管百分率(TWPV％)和丙二醛(MDA)，而使血浆超氧化物歧化酶(SOD)活性降低。控制光照使SOD活性升高而显著降低了PHS发病率、RV／TV、TWPV％和MDA。减轻体内脂质过氧化作用，提高机体抗氧化酶的活性和减轻以非肌型肺动脉肌型化为特征肺血管重构，可能是间歇光照降低肉鸡PHS发病率的部分机制。
试验Ⅲ间歇光照对低温诱导的肉鸡肺细小动脉血管重构及其PKCα表达的影响。观察在低温环境下间歇光照对肉鸡肺细小动脉蛋白激酶Cα(PKCα)表达的影响及其与肺血管重构的关系。320羽肉鸡随机分为四个组。常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。测定RV／TV、MDA、SOD、WA／TA、mMTPA、红细胞压积(PCV)；采用免疫组化方法标记肺动脉PKCα，以OD值代表PKCα的表达。结果环境低温使肉鸡PHS发病率升高，RV／TV、WA／TA、mMTPA、MDA值和肺细小动脉PKCα的OD值显著升高，而间歇光照能够有效地降低寒冷诱发的PHS发病率和上述指标。肺小动脉PKCα的表达从23日龄起与mMTPA和WA／TA呈正相关，并且具有显著性。寒冷诱使肉鸡肺小动脉PKCα表达的上调可能参与了肺血管重构的形成过程，间歇光照抑制肺血管重构可能与PKCα下调有关。
试验Ⅳ间歇光照对低温诱导的肉鸡肺细小动脉血管重构及其PDGF-β受体表达的影响。观察在低温环境下间歇光照对肉鸡肺细小动脉PDGF-β受体表达的影响，及其与肺血管重构的关系。320羽肉鸡随机分为四个组，常温组按常规饲养；低温三个组采用低温诱发PHS，并于9d～30d分别在夜间停止光照0、3、5h，以后恢复连续光照。测定PCV、WA／TA和mMTPA等指标；采用免疫组化方法标记肺动脉PDGF-β受体，以OD值代表PDGF-β受体的表达。结果环境低温使PDGF-β受体表达上调，WA／TA和mMTPA值也显著升高，而间歇光照明显抑制血管重构，并且使肺动脉PDGF-D受体的OD值降低。PDGF-β受体的表达从23日龄开始与mMTPA和WA／TA呈正相关，并且具有显著性。PDGF-β受体表达上调可能与低温所致肺小动脉重构有密切关系，而间歇光照减轻肉鸡肺血管重构可能与抑制PDGF-β受体表达有关。
试验Ⅴ间歇光照对低温诱导的肉鸡肺细小动脉血管重构及其PCNA表达的影响。观察在低温环境下间歇光照对肉鸡肺细小动脉增殖细胞核抗原(PCNA)表达的影响，并探讨PCNA与肺血管重构的关系。320羽肉鸡随机分为四个组，常温组按常规饲养；低温三个组采用低温诱发PHS，并于9 d～30 d分别在夜间停止光照0、3、5 h，以后恢复连续光照。测定WA／TA和mMTPA等指标；采用免疫组化方法标记PCNA，图像分析软件分别计数每条血管中膜PCNA阳性细胞数和细胞总数，求出百分数即为增殖指数(PI)。结果环境低温使肺动脉的WA／TA和mMTPA值和PCNA值显著升高，而间歇光照能够有效地减轻寒冷诱发的肺动脉重构和PCNA值。在肉鸡快速生长的早期采用间歇光照能够抑制寒冷所致的肺血管重构可能与抑制肺动脉平滑肌细胞增殖有关。
试验Ⅵ添加呋喃苯胺酸对低温诱导的肉鸡肺动脉高压综合征的发病率及肺血管重构的影响。观察在低温环境下呋喃苯胺酸对肉鸡PHS的防治效果及其对肺血管重构的影响。240羽肉鸡于14 d时随机分为A、B和C三组分置于两个鸡舍。A组按常规饲养，B组和C组采取低温诱发PHS，并从30 d至44 d B组不添加药物而C组于日粮中添加0.015％的呋喃苯胺酸。记录每周PHS发病数、体重。定期测定RV／TV、PCV、WA／TA和mMTPA等各项值。结果饲料中添加呋喃苯胺酸降低了寒冷诱发的PHS发病率。B组RV／TV、WA／TA和mMTPA值显著升高，而C组使之降低，并在44 d差异显著；C组体重显著低于B组。降低肺动脉压，抑制以肺动脉壁肥厚为特征的血管重构可能是呋喃苯胺酸有效降低低温所致PHS发病率的部分机制。
试验Ⅶ维生素C对常温下肉鸡肺动脉高压综合征发病率及肺血管重构的影响。观察在常温环境下维生素C对肉鸡PHS的防治效果及其对肺血管重构的影响。150羽肉鸡于21 d时随机分为C、T1和T2组，按常规饲养，C组不添加药物，T1组和T2组分别从21 d至37 d在饲料中添加维生素C 200 mg／kg和500 mg／kg。统计PHS的死亡数并定期称重。测定RV／TV、PCV、MDA、SOD、WA／TA和mMTPA等指标。结果与对照组相比，T1组PHS死亡率和RV／TV值显著降低，80-200微米肺动脉WA／TA和mMTPA值显著降低，PCV和MDA值极显著降低。T2组PHS死亡率与对照组相同，PCV值显著降低，50-80微米肺动脉的WA／TA和mMTPA值极显著高于对照组，MDA水平极显著高于对照组而SOD值显著降低。降低PCV值、清除体内过多的氧自由基及减轻肺血管重构可能是低剂量维生素C有效防治PHS的部分机制，而使氧自由基产生增多，导致肺血管重构可能是高剂量VC防治PHS失败的部分原因
试验Ⅷ蛋白激酶C抑制剂Calphostin C对PDGF-BB诱导的肉鸡肺动脉血管平滑肌细胞增殖的影响．探讨蛋白激酶C抑制剂Calphostin C对血小板源生长因子(PDGF-BB)诱导的肉鸡肺动脉平滑肌细胞(PASMC)增殖的影响。肉鸡肺动脉平滑肌细胞体外培养，用PDGF-BB刺激PASMC，采用细胞记数法和流式细胞仪测定Calphostin C对PASMC增殖的影响．结果Calphostin C显著地抑制PDGF-BB诱使的PASMC增殖，使细胞生长停滞于G_0／G_1期。蛋白激酶C抑制剂Calphostin C抑制了PASMC增殖，提示PDGF-BB刺激血管平滑肌细胞增殖与PKC信号传导通道有关，Calphostin C可能作为防治肺血管重构的一种药物。
试验ⅨX／X0体系作用的肺动脉内皮细胞条件培养液对内鸡肺动脉平滑肌细胞的促增殖作用及褪黑激素对其的影响。观察黄嘌呤-黄嘌呤氧化酶(xanthine-xanthineoxidase，X-XO)条件培养液对肉鸡肺血管平滑肌细胞是否有促增殖作用，及褪黑激素能否抑制其增殖。肉鸡肺动脉平滑肌细胞与X／XO内皮细胞条件培养液共培养刺激PASMC，采用流式细胞仪测定X／XO条件培养液和褪黑激素对PASMC增殖的影响，并检测培养液中的丙二醛(MDA)含量。与正常内皮细胞条件培养基相比，X／XO条件培养基促使PASMC发生增殖，并从G_0／G_1期进入S和G_2／M期，其培养液中MDA含量显著高于对照组；当预先加入褪黑激素时，抑制了X／XO条件培养液的促平滑肌细胞增殖作用，G_0／G_1期细胞比例提高，而S期、G_2／M期细胞减少。褪黑激素组细胞培养液中MDA含量显著低于X／XO模型组。清除培养液中的氧自由基可能是褪黑激素抑制X／XO条件培养液诱导肉鸡肺动脉平滑肌细胞增殖的机制之一。
Despite investigation of the syndrome for many years, ascites or pulmonary hypertension syndrome (PHS) is still a condition that inflicts financial loss on poultry farmers around the world. Approximately 4% of all broilers die from PHS, amounting to a loss estimated at $1 billion annually. So, prevention and cure of PHS are especially important. There are multiple aetiologies of pulmonary hypertension syndrome(PHS). The main cause of which is rapid growth. Thus every drug has its limit to cure the disease. Remanet of drug in meat also is a problem. Early feed restriction could slow broiler growth at early age, reduce ascites incidence, but could induce stress too. Lighting restriction at early age could decrease ascites incidence and stress effectively.
1 light (L):3dark (D) lighting program is recognized as best schedule to prevent ascites, but is difficult to apply in China. To implore a simple and effective lighting schedule would be of benefit to prevent ascites. Since the mechanism of Lighting restriction remain unclear, The choose of lighting schedules are difficult.
In recent years, most ascites research has centred on production capability and ascites incidence of broilers. The investigations on the aetiology of ascites in chickens include oxygen level, thyroxin, growth hormone and cortin. Pulmonary vascular remodeling is an important pathological feature of hypoxia pulmonary hypertension in mammal, leading to increased pulmonary vascular resistance and reduced compliance. Since vascular remodeling becomes progressively more important as the disease advances, an possibly more fruitful approach may be to target pulmonary vascular remodeling. It has been fould that Pulmonary vascular remodeling also occurred in PHS in broilers. It's mechanism remain unclear. The present study was conducted to evaluate the association of changes of protein kinase Ca (PKCa), platelet-derived growth factor BB(PDGF-BB) and its receptor (PDGF-βreceptor)、proliferating cell nuclear antigen (PCNA) and oxygen free radical(OFR) with alterations in pulmonary vascular structure for understanding the pathogenesis of pulmonary vascular remodeling in vito and in vitro, to implore the effect of intermittent lighting schedule、furosemide and vitamin C on pulmonary vascular remodeling respectively. If PKC-a and PDGF actually play a critical role in pulmonary vascular remodeling. Both of them may be to target pulmonary vascular remodeling.
Test 1 Effects of intermittent lighting schedules on incidence of pulmonary hypertension syndrome and pulmonary vascular remodeling in broilers.The purpose of the present study was to examine the efficacy of imposing intermittent lighting schedules on reduction of the incidence of ascites(or Pulmonary Hypertension Syndrome,PHS)induced by cool ambient temperature and to investigate its effect on the pulmonary vascular remodeling of broiler chickens. A total of three hundred and twenty broilers were randomly allocated to four rooms at 9 days of age. In one room, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L: 0D and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce PHS. PHS cases, body weights and feed intake were measured weekly for each group. The ratio of vessel wall area to total area (WA/TA) and mean medial thickness in pulmonary arterioles (mMTPA) were determined . The results indicated that the cool ambient temperature could increase morbidity of PHS in broilers, the values of WA/TA and mMTPA also were increased significantly, whereas the IL schedule could successfully decrease the morbidity of PHS and the values of WA/TA and mMTPA. Birds in IL groups were lighter than that in LC group during light restriction period, but both the final body weights and total feed conversion ratio were not significantly affected by the lighting program in all birds subjected to low temperature. It is concluded that introduction of IL schedules during the early growing period is of benefit to reduce PHS morbidity induced by cool ambient temperature in fast-growing broilers, and attenuated pulmonary vascular remodeling may be involved in the underlying mechanisms.
Test 2 Effects of intermittent lighting schedules on the incidence of ascites, the lipid peroxidation and enzymatic antioxidant activity of broilers. The purpose of the present study was to examine the efficacy of intermittent lighting schedules at night in reducing the incidence of ascites induced by cool environment and to test its effect on the lipid peroxidation and activity of enzymatic antioxidant in broilers. A total of three hundred and twenty broilers were randomly aUocated to four rooms at 9 days of age. In one Toom, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L:0D and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce pulmonary hypertension syndrome(PHS). The results showed that Low temperature significantly increased RV/TV and the ascites morbidity, so were the plasma MDA concentration and the percentages of TWPV. Whereas the plasma SOD activity was decreased. The intermittent lighting (IL) schedules had successfully reduced PHS in broilers. The values of RV/TV, plasma MDA concentration and the percentages of TWPV were reduced significantly, whereas the activity of the plasma SOD were significantly promoted. Body weights (BW) were reduced significantly by light restriction at 20 days of age. However, IL broilers exhibited compensatory growth during the finisher period in such a way that at Day 44, a similar BW as that of their CL counterparts was attained. The results indicated that alleviated the lipid peroxidation, enhanced the enzymatic antioxidant activity and reduced the percentages of the TWPA may be the part mechanism of intermittent lighting (IL) schedule reduced ascites of broiler.
Test 3 Effects of intermittent lighting schedules on expression of PKCa in pulmonary arterioles and its association with pulmonary vascular remodeling in broilers induced by cold temperature. The purpose of the present study was to examine the effects of intermittent lighting schedules on expression of protein kinase C a (PKC a) in pulmonary arterioles in broilers exposed to cold temperature and its relationship with pulmonary vascular remodeling. A total of three hundred and twenty broilers were randomly allocated to four rooms at 9 days of age. In one room, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L: OD and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce pulmonary hypertension syndrome(PHS). PHS incidence was recorded. Malonilaldehyde (MDA) concentration,packed cell volume (PCV), Mean medial thickness (mMTPA), Ratio of vessel wall area to total area (WA/TA) and right to total ventricle (RV/TV) were determined. The expression of PKCa in the pulmonary arterioles labeled by immunohistochemistry and quantified by measuring optical density (OD). The results indicated that the cool ambient temperature could increase morbidity of PHS in broilers. The value of MDA, WA/TA and mMTPA were increased significantly, the same as the OD value of PKCa, whereas the IL schedules could successfully decrease the morbidity of PHS .The value of WA/TA ,mMTPA, MDA and PKCa were decreased too. It was concluded that cold exposure enhanced arterioles PKCa expression, which might involved in the underlying mechanisms of pulmonary vascular remodeling. The introduction of IL schedules were of benefit to attenuate pulmonary vascular remodeling ,which may be correlated with the decrease of PKC a expression.
Test 4 Effects of intermittent lighting schedules on expression of PDGF-βreceptor in pulmonary arterioles and its association with pulmonary vascular remodeling in broilers induced by cold ambient temperature. The purpose of the present study was to examine the effects of intermittent lighting schedules on expression of platelet-derived growth factorβreceptor (PDGF-βreceptor) in pulmonary arterioles in broilers exposed to cold temperature and its relationship with pulmonary vascular remodeling. A total of three hundred and twenty broilers were randomly allocated to four rooms. In one room, the continuous lighting schedule (CL) of 24 L: 0D was maintained, ambient temperature kept normal (group NC),while in other three rooms ,the chickens were subjected to cool ambient temperature to induce PHS. The continuous lighting schedule of 24 L:0D (group LC) and the intermittent lighting (IL) schedule of 21 L:3 D(group L1) and 19 L:5 D (group L2) were imposed respectively from 9 to 30 days of age. PHS incidence was recorded. Mean medial thickness (mMTPA), ratio of vessel wall area to total area (WA/TA) in pulmonary arterioles ,ratio of right to total ventricle (RV/TV), malonilaldehyde (MDA) concentration and packed cell volume (PCV) were determined respectively. The expression of PDGF-βreceptor in the pulmonary arterioles labeled by immunohistochemistry and quantified by measuring optical density (OD). The results indicated that the cool ambient temperature could increase the value of WA/TA and mMTPA in pulmonary arterioles, the same as the OD value of PDGF-βreceptor, whereas the intermittent lighting (IL) schedule could successfully decrease the value of WA/TA、mMTPA and PDGF-βreceptor. It was concluded that cold exposure enhanced PDGF-β receptor expression in pulmonary arterioles, which might involved in the underlying mechanisms of pulmonary vascular remodeling. The introduction of intermittent lighting schedules were of benefit to attenuate pulmonary vascular remodeling , which may be correlated with the decrease of PDGF-βreceptor expression in pulmonary arterioles.
Test 5 Effects of intermittent lighting schedules on expression of PCNA in pulmonary arterioles and its association with pulmonary vascular remodeling in broilers induced by cold temperature. The objection of the present study was to examine the effects of intermittent lighting schedules on expression of proliferating cell nuclear antigen (PCNA) in pulmonary arterioles in broilers exposed to cold temperature and its relationship with pulmonary vascular remodeling. A total of three hundred and twenty broilers were randomly allocated to four rooms at 9 days of age. In one room, the continuous lighting (CL) schedule of 24 L:0D was maintained, and ambient temperature was kept normal. While in other three rooms continuous lighting (CL) schedule of 24L: 0D and intermittent lighting (IL) schedules of 21L:3 D and 19L:5D dark were imposed respectively during the night from 9 to 30 days of age. Chickens in the later three rooms were subjected to low temperature to induce pulmonary hypertension syndrome(PHS). PHS incidence was recorded. The mean medial thickness (mMTPA), ratio of vessel wall area to total area (WA/TA) in pulmonary arterioles ,Ratio of right to total ventricle (RV/TV), packed cell volume (PCV) were determined. The expression of PCNA in the pulmonary arterioles labeled by immunohistochemistry and quantified by counting the number of the positive PCNA cells and total vascular smooth ceils using computer-image analytic software and then calculating the PCNA index (PI). The results indicated that the cool ambient temperature could increase the value of WA/TA and mMTPA significantly, the same as the PI, whereas the IL schedules could successfully attenuate pulmonary vascular remodeling and PI. It was concluded that introduction of intermittent lighting schedule during the early growing period was of benefit to attenuate pulmonary vascular remodeling induced by cool ambient temperature in fast-growing broilers, and the inhibition of vascular smooth cell proliferation might be involved in the underlying mechanisms.
Test 6 Effects of dietary furosemide on incidence of pulmonary hypertension syndrome and pulmonary vascular remodeling in broilers induced by cool environmental temperatures. The objective of the present study was to evaluate the influence of dietary furosemide (FURO) on the incidence of Pulmonary Hypertension Syndrome(PHS) induced by cool ambient temperature and to investigate its effect on the pulmonary vascular remodeling of broiler chickens. A total of two hundred and forty broilers were randomly allocated to three groups. The birds in group A were fed a grower diet and kept in normal ambient temperature from 14 to 44 day of age. Group C and group B were subjected to cool ambient temperature to induce PHS and were fed a grower diet with (group C) or without 0.015 percent furosemide (group B) from 30 to 44 day of age. PHS incidence, body weights were measured weekly for each group. Heart, Lung and blood samples were taken from 10 birds per group randomly selected at 14, 23, 30, 37 and 44 days of age, for the determination of the ratio of vessel wall area to total area (WA/TA), mean medial thickness in pulmonary arterioles (mMTPA), etc. It was found that birds exposed to cold had higher PHS morbidity. However, it was reduced by dietary furosemide supplementation. The value of right to total ventricular weight ratios (RV/TV) and packed red blood cell volume (PCV) in group B were significantly higher than that in group A, also were the value of WA/TA and mMTPA which served as describing pulmonary vessel remodeling. Birds fed 0.015 percent furosemide had significantly lower RV/TV, WA/TA and mMTPA than that in group B, also were body weights, whereas PCV were increased. It was concluded that dietary furosemide reduced morbidity of PHS induced by cool ambient temperature, presumably by reducing pulmonary arterial pressure. Attenuated pulmonary vascular remodeling might be involved in the underlying mechanisms too.
Test 7 Effects of dietary vitamin C on mortality of pulmonary hypertension syndrome and pulmonary vascular remodeling in broilers under normal environmental temperatures. The objective of the present study was to evaluate the influence of dietary vitamin C on the mortality of pulmonary hypertension syndrome(PHS) under normal ambient temperature and to investigate its effect on the pulmonary vascular remodeling of broiler chickens. A total of one hundred and fifty broilers were randomly allocated to three groups in one room, in which temperature kept normal. From 21 to 37d, the birds in control group (C) were fed a grower diet, treat 1 (T_1) and treat 2 group(T_2) were fed a grower diet with 200mg/kg and 500mg/kg respectively. PHS mortality and body weights were measured weekly for each group. Heart, Lung and blood samples were taken for the determination of SOD and MDA concentration in blood plasma, packed cell volume (PCV), mean medial thickness in pulmonary arterioles (mMTPA), and the ratio of vessel wall area to total area (WA/TA), right ventricle to total ventricular weight. It was found that birds fed 200mg/kg vitamin C had lower PHS mortality than that in group C. The value of WA/TA、mMTPA of pulmonary artery with outer diameter from 80 to 200μm and PCV vaule were significantly reduced, also were the MDA level, whereas SOD concentration were significantly increased. The birds fed 500mg/kg vitamin C had same PHS mortality as control group. The percentages of WA/TA and mMTPA of pulmonary artery with outer diameter from 50 to 80μm and the concentration of MDA were increased significantly, whereas PCV and SOD concentration were reduced. It was concluded that decreasing PCV value, weeding up extra oxygen free radical (OFR) and attenuating pulmonary artery remodeling might be involved in the underlying mechanisms of prevention PHS by low dose vitamin C, Whereas promoting OFR level and inducing pulmonary artery remodeling might be the cause of high dose vitamin C failing to prevent PHS.
Test 8 Effects of protein kinase C inhibitor-Calphostin C on proliferation induced by PDGF-BB in pulmonary artery smooth muscle cells of broilers. To xplore the effects of protein kinase C inhibitor-Calphostin C on proliferation in pulmonary artery smooth muscle cells (PASMC) of broilers induced by PDGF-BB. Pulmonary vascular smooth muscle cells were cultured in vitro and stimulated by PDGF-BB. The effects of Calphostin C on PASMC proliferation were analyzed by using flowcytomerty and cell counting. The PASMC proliferation induced by PDGF-BB was significantly inhibited by Calphostin C and the cells were stagnated on G_0/G_1 phase. The result of Calphostin C inhibition on the PASMC proliferation suggested that proliferation induced by PDGF-BB may be correlated with PKC pathway. Calphostin C may be an agent for prevention of vascular remodeling.
Test 9 Effects of melatonin on proliferation of pulmonary artery smooth muscle cells in broilers induced by xanthine-xanthine oxidase conditioned medium. To investigate the effects of X/XO conditioned medium on proliferation of pulmonary artery smooth muscle cells (PASMC) in broilers, and melatonin could or not attenuate PASMC proliferation induced by X/XO conditioned medium. Pulmonary artery smooth muscle cells were cultured in vitro with X/XO endothelial cells conditioned medium to induce proliferation of PASMC. The effect of melatonin on PASMC proliferation were analyzed using flowcytomerty. The MDA level in medium were detected. Compared to normal PAEC medium, X/XO conditioned medium lead to PASMC proliferation, stimulate PASMC from G_0/G_1 phase to S and G_2/M phase. The MDA level in PASMC cultured with X/XO conditioned medium were significantly higher than that in PASMC cultured with normal PAEC medium. The PASMC proliferation induced by X/XO conditioned medium was successfully inhibited by melatonin, which added in medium ahead, and the number of cells on G_0G_1 phase were higher, whereas on S and G_2/M phase lower. The MDA level in melatonin group was less than X/XO group. Eliminating of OFR may be involved in the underlying mechanisms of the melatonin on inhibiting proliferation of PASMC in broilers induced by X/XO conditioned medium.
引文
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[1] Cowan K N, Jones P L, and Rabinovitch M. Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis [J]. Circ Res, 1999, 84: 1223-1233.
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[1] 何诚，赵德明，梁礼成．低温高能日粮对肉鸡肺动脉和腹水症的影响[J]．畜牧兽医学报，2000，31(1)：34-40．
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