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血管紧张素1-7对博来霉素诱导大鼠肺纤维化的抑制作用

Anti-fibrotic effects of angiotensin1-7 on bleomycin-induced pulmonary fibrosis in rats

摘要:

目的 探讨血管紧张素(Ang) 1-7对博来霉素诱导大鼠肺纤维化的抑制作用.方法 18只Wister雄性大鼠按随机数字表法随机分为对照组、博来霉素组和博来霉素+Ang1-7组.均以微量泵0.29 μl/h皮下24 h恒速持续泵注4周,具体为:博来霉素组以博来霉素气管内滴入并泵内注入注射用水,博来霉素+ Ang1-7组以博来霉素气管内滴入并泵内注入Ang1-7(25 μg·kg-1·h-1),对照组以生理盐水气管内滴入并泵内注入注射用水.4周后HE、Masson染色评价纤维化程度,测定羟脯氨酸含量,Western印迹法分析检测Ⅰ型胶原蛋白,实时定量聚合酶链反应(RT-PCR)检测转化生长因子(TGF)-β及α-Ⅰ型胶原mRNA含量.培养人胚肺成纤维细胞(HFL-1),设置无刺激对照组、AngⅡ刺激组(10-7 mol/L的AngⅡ刺激)、Ang1-7刺激组(10-7mol/L的Ang 1-7刺激)、AngⅡ+Ang1-7刺激组(上述浓度的Ang1-7和AngⅡ刺激)、AngⅡ+Ang1-7+ A779刺激组(10-6mol/L的A779干预1h后予上述浓度Ang1-7和AngⅡ刺激).利用QuantiGene多基因定量检测下游因子TGF-β1、RT-PCR检测α-Ⅰ型胶原mRNA表达情况.结果 体内实验:与对照组比较,博来霉素组纤维化程度增高,组织中羟脯氨酸的含量明显增多[(3.69±0.18)比(0.50±0.15) mg/g,P<0.05];博来霉素+ Ang1-7组纤维化程度减轻,羟脯氨酸含量[(2.14±0.29) mg/g]明显减少(P<0.05);博来霉素组TGF-β1 mRNA、α-Ⅰ型胶原mRNA和α-Ⅰ型胶原蛋白相对表达量分别为4.45 ±0.45、5.14±0.55和1.48±0.34,均高于对照组的1.00±0.20、1.00±0.08和0.23 ±0.11(均P<0.05);而博来霉素+ Ang1-7组上述表达量(2.80±0.35、3.10±0.52和0.49±0.11)均低于博来霉素组(均P<0.05).体外实验:AngⅡ刺激组TGF-β1 mRNA和α-Ⅰ型胶原mRNA的相对表达量(1.67±0.26和4.86±1.36)均高于无刺激对照组(1.00±0.10和1.46±0.54)(均P<0.05);而Ang1-7刺激组上述表达量(1.30±0.22和2.07±1.05)与无刺激对照组差异均无统计学意义(均P>0.05);AngⅡ+ Ang1-7 刺激组上述表达量(0.91±0.30和1.57±0.27)均低于AngⅡ刺激组(均P<0.05);AngⅡ+ Ang1-7+A-779刺激组上述表达量(1.25 ±0.14和1.29±0.49)与AngⅡ+Ang1-7刺激组差异均无统计学意义(均P>0.05).结论 Ang 1-7对博来霉素所致的肺纤维化具有抑制作用,该作用可能与Ang 1-7抑制AngⅡ诱导TGF-β1的表达有关.

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abstracts:

Objective To explore the anti-fibrotic effects of angiotensin (Ang) 1-7 on bleomycin (BLM)-induced pulmonary fibrosis in rats.Methods Eighteen Wister male rats were randomly divided into 3 groups,including control group (intratracheal instillation with physiological saline and subcutaneous micropump with bi-distilled water at the rate of 0.29 μl/h),BLM group (intratracheal instillation with bleomycin and subcutaneous micro-pump with bi-distilled water at the same rate) and BLM + Ang1-7 group (intratracheal instillation with bleomycin and subcutaneous micro-pump with Ang1-7 at a dose of 25 μg ·kg-1 · h-1 at the same rate).At Day 28,lung tissues were collected.Histological changes of lungs were evaluated by hematoxylin and eosin and Masson's trichrome stains.Collagen content of lung tissues was assessed by hydroxyprolin concentration.Then the products of protein and RNA were collected.And Western blot and realtime polymerase chain reaction (RT-PCR) were used to detect the protein or mRNA of TGF-β1 and α-collagen Ⅰ.Human embryonic lung fibroblast (HFL-1) was divided into 5 groups:(1) control group:no stimulation; (2) AngⅡ group:stimulation of AngⅡ (10-7mol/L) ; (3) Ang1-7 group:stimulation of Ang1-7 (10-7mol/L) ; (4) Ang1-7 plus AngⅡ group:stimulation by AngⅡ (10-7mol/L) with Ang1-7 (10-7mol/L) pre-treatment; (5) Ang1-7 +AngⅡ + A-779 group:stimulation by AngⅡ and Ang1-7 (10-7 mol/L) with Mas receptor inhibitor A-779 (10-6mol/L) pre-treatment.Then the products of protein and RNA were collected.And QuantiGene and RT-PCR were used to detect the activation of TGF-β1,and α-collagen Ⅰ mRNA.Results Compared with control group,fibrosis score and hydroxyproline concentrations increased significantly in BLM group,but declined in BLM + Ang1-7 group.The difference was statistically significant (P < 0.05).TGF-β1 mRNA,α-collagen Ⅰ mRNA and α-collagen Ⅰ protein level were up-regulated by BLM (4.45 ± 0.45 vs 1.00 ± 0.20,5.14 ± 0.55 vs 1.00 ± 0.08,1.48 ±0.34 vs 0.23 ± 0.11) (all P < 0.05) ; while compared with BLM group,those of BLM +Ang1-7 group were down-regulated (2.80 ± 0.35,3.10 ± 0.52,0.49 ± 0.11) (all P < 0.05).In vitro:TGF-β1 mRNA and α-collagen Ⅰ mRNA level were up-regulated by AngⅡ (1.67 ±0.26 vs 1.00 ±0.10,4.86 ± 1.36 vs 1.46 ± 0.54) (all P < 0.05) ; while those of Ang Ⅱ + Ang1-7 group were down-regulated (0.91 ± 0.30,1.57 ± 0.27) compared with Ang Ⅱ group (all P < 0.05) ; no significant difference existed between the Ang Ⅱ + Ang1-7 + A-779 group (1.25 ± 0.14,1.29 ± 0.49) and Ang Ⅱ + Ang1-7 group (P > 0.05).Conclusion Ang1-7 has anti-fibrous effect upon bleomycin-induced pulmonary fibrosis in rats andsuch an effect of Ang1-7 may be associated with Ang Ⅱ-induced expression of TGF-β1.

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作者: 孟莹 [1] 余常辉 [1] 蔡绍曦 [1] 李旭 [2]
期刊: 《中华医学杂志》2013年93卷20期 1585-1589页 MEDLINEISTICPKUCSCD
栏目名称: 基础研究
DOI: 10.3760/cma.j.issn.0376-2491.2013.20.020
发布时间: 2013-07-11
基金项目:
国家自然科学基金 广东省科技计划项目
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