缺氧对体外培养的早孕期细胞滋养细胞中缺氧适应相关部分基因表达及细胞浸润能力的调控

目的:探讨缺氧对细胞滋养细胞表达缺氧诱导因子-1α(HIF-1α)及氧感受器缺氧诱导因子脯氨酸羟化酶1、2(HPH/PHD1、2)和抑制缺氧诱导因子-1(FIH-1)的调控,以及缺氧对体外培养的细胞滋养细胞浸润能力的调节。方法:用RT-PCR和Western blot法检测在常氧、缺氧再复氧及持续缺氧等条件下,细胞滋养细胞中HIF-1α、HPH/PHD1、2和FIH-1 mRNA和蛋白表达的变化;并用体外侵袭实验检测缺氧再复氧、持续低氧对细胞滋养细胞浸润能力的影响。结果:(1)持续缺氧条件下培养的细胞滋养细胞HIF-1α和HPH/PHD2 mRNA和蛋白表达显著高于常氧组(P<0.01);HPH/PHD1和FIH-1 mRNA和蛋白表达显著低于常氧组(P<0.01)。缺氧再复氧后培养的细胞滋养细胞HIF-1α和HPH/PHD2 mRNA和蛋白表达显著高于常氧组(P<0.05),但显著低于持续缺氧组(P<0.05);HPH/PHD1和FIH-1 mRNA和蛋白表达均显著低于常氧组(P<0.05),但显著高于持续缺氧组(P<0.05)。(2)持续缺氧显著抑制细胞滋养细胞的浸润能力,与常氧组比较明显降低(P<0.01);缺氧后再复氧细胞滋养细胞的浸润能力居中,与常氧组比较明显降低(P<0.05);与持续缺氧组比较明显升高(P<0.05)。结论:滋养细胞可感受氧分压变化,HIF-1α、HPH/PHD1、HPH/PHD2和FIH-1相互作用与滋养细胞浸润能力调节有关。     

尼可地尔对大鼠低氧性肺高压的影响

目的:探讨线粒体ATP敏感性钾通道开放剂(mitoKATPCO)尼可地尔(nicorandil)对大鼠低氧性肺动脉高压的影响?方法:将40只大鼠随机分成对照组(C组)?低氧组(H组)?低氧+尼可地尔组(N组)与低氧+尼可地尔+5-羟基葵酸盐组(HD组),后3组置于常压低氧仓内,每周6 d,每天8 h,持续4周后测定各组大鼠平均肺动脉压(mPAP),右心肥厚指数RV/(V+S),HE染色观察肺小动脉血管壁的病理变化并检测增殖相关抗原(PCNA)?结果:慢性缺氧可诱导大鼠mPAP及RV/(LV+S)升高,大鼠肺小血管增厚重构,PCNA表达增加,尼可地尔可显著抑制上述变化,且该效应可被线粒体KATP(mitoKATP)通道特异性阻断剂5-羟基葵酸盐阻断?结论:尼可地尔通过开放mitoKATP通道降低肺动脉压,拮抗右心肥厚,并抑制肺血管增殖重构,治疗低氧性肺高压?     

缺氧适应相关基因在不同妊娠阶段滋养层组织中的表达

目的:探讨缺氧诱导因子脯氨酸羟化酶1(HPH1/PHD1)和缺氧诱导因子-1抑制因子(FIH-1)在不同妊娠阶段中的作用。方法:采用RT-PCR和Western blotting方法从mRNA和蛋白水平比较分析14例10周以内妊娠者(早孕A组)、11例10-12周妊娠者(早孕B组)、8例中期妊娠者(中孕组)和24例正常晚期孕妇(晚孕组)滋养层组织中的HPH1/PHD1和FIH-1的表达差异。结果:①在不同妊娠时期滋养层组织中均有HPH1/PHD1和FIH-1 mRNA及蛋白的表达,且均是早孕A组最低,早孕B组明显升高并达到峰值,此后逐渐下降,但均高于早孕A组的水平(P均<0.01)。②在妊娠期的各个阶段,HPH1/PHD1的mRNA和蛋白表达水平均强于FIH-1的表达,并均呈显著正相关;PH1/PHD1 mRNA与其蛋白间和FIH-1 mRNA与其蛋白间也呈显著正相关。结论:HPH1/PHD1与FIH-1可能在妊娠进展过程中氧分压变化的情况下通过调节HIF-1的表达和翻译参与对滋养细胞浸润和增殖的调控,参与胎盘发育,对于妊娠成功起重要调节作用。     

Hypoxic Pulmonary Hypertension (HPH) and Iptakalim,a Novel ATP‐sensitive Potassium Channel Opener Targeting Smaller Arteries in Hypertension

Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating chronic disorder of the pulmonary circulation. Attempts to use drugs in the therapy of hypoxic pulmonary hypertension indicated the importance of prevention or reduction of vasoconstriction as well as of the reversal of remodeling within the cardiovascular system. Iptakalim (2,3‐dimethyl‐N‐(1‐methylethyl)‐2‐butylamine), a novel ATP‐sensitive potassium channel opener, has the desired effects on hypoxic pulmonary arteries. Iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Moreover, iptakalim has selective antihypertensive effects: it significantly lowers arterial pressure in hypertensive animals, but has little if any effect in normotensive animals. In HPH iptakalim has selective effects on smaller arteries. Long‐term iptakalim therapy decreases expression of sulfonylurea receptor 2 and of mRNA of inwardly rectifying potassium channel in smaller arteries of spontaneously hypertensive rats. Iptakalim inhibits the effects of endothelin‐1, reduces the intracellular calcium concentration and inhibits the cell cycle in smooth muscle cells of pulmonary arteries. There is no evidence for the development of tolerance to the long‐lasting antihypertensive action of iptakalim. At therapeutic doses iptakalim has no effects on the central nervous, respiratory, digestive, or endocrine systems. It has a broad therapeutic range, so that it can be safely used in the therapy of HPH.     

Hyperoxia attenuates the inhibitory effect of nitric oxide donors on HIF prolyl-4-hydroxylase-2: Implication on discriminative effect of nitric oxide on HIF prolyl-4-hydroxylase-2 and collagen prolyl-4-hydroxylase

Prolyl 4-hydroxylases (P4Hs), such as collagen prolyl-4-hydroxylases (CPHs) and hypoxia inducible factor prolyl-4-hydroxylases (HPHs), have recently been recognized as promising drug targets for the treatment of fibrotic and ischemic diseases. CPHs and HPHs catalyze identical metabolic reactions, yet lead to quite different physiological consequences, collagen synthesis and the regulation of oxygen homeostasis. Selective modulation of the two enzymes should provide a therapeutic benefit upon pharmacotherapy. In an in vitro VHL capture assay, hydroxylation of the 19mer HIF peptide (corresponding to HIF-1α residues 556–574) by HPH-2 was effectively prevented by nitric oxide (NO) donors, (±)-S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione. The NO donors also caused inhibition of HPHs and accumulation of nonhydroxylated HIF-1α protein in A549 human lung adenocarcinoma cells. Hyperoxia (100% O₂) attenuated both NO donor-induced accumulation of HIF-1α and inhibition of HPH-mediated hydroxylation. In the presence of a proteasome inhibitor, MG132, the hyperoxia-mediated degradation of HIF-1α was deterred and hydroxylated HIF-1α was detected. SNAP, while being an effective inhibitor of proline 4-hydroxylation of HIF-1α by HPH-2, did not diminish proline hydroxylation of collagen by CPHs. Our data suggest that NO inhibits HPH-2 via competing with dioxygen and that the discriminative effect of NO on CPHs and HPH-2 is attributable to the difference in the affinity of the two enzymes toward dioxygen.     

CircRNA-Tbpl1海绵吸附miR-214-3p调控自噬在低氧性肺动脉高压血管重塑中的作用及其机制何梦,孙健,沈巨信,秦娥

目的 探讨circRNA-Tbpl1通过海绵吸附miR-214-3p调控自噬在低氧性肺动脉高压血管重塑中的作用,并分析其机制。方法 构建低氧性肺动脉高压(hypoxic pulmonary hypertension, HPH)小鼠模型,分离小鼠原代肺动脉平滑肌细胞(PASMCs)。低氧处理PASMCs,CCK-8检测细胞活性,Western blot检测自噬相关蛋白表达,qRT-PCR检测circRNA-Tbpl1的相对表达水平。通过转染和自噬诱导剂雷帕霉素(rapamycin, Rap)干预,分析circRNA-Tbpl1与PASMCs自噬的相关性。通过共转染sh-circRNA-Tbpl1和miR-214-3p抑制物,分析circRNA-Tbpl1/ miR-214-3p对低氧诱导的PASMCs自噬和细胞增殖活性的影响。结果 与对照组小鼠相比,HPH小鼠的右心室收缩压(right ventricular systolic pressure, RVSP)、右心室肥厚指数(right ventricular hypertrophy index, RVHI)显著增加,且HPH小鼠肺血管出现明显的中膜肥大和外膜增生,明显出现肺血管重塑。HPH小鼠的肺组织和低氧处理的PASMCs中LC3 II、Beclin-1表达水平显著上调,p62表达下调,circRNA-Tbpl1水平升高。下调circRNA-Tbpl1可抑制低氧诱导的PASMCs自噬,减弱细胞增殖活性。双荧光素酶报告基因检测结果显示circRNA-Tbpl1海绵吸附miR-214-3p,miR-214-3p在HPH小鼠和低氧诱导的PASMCs中表达降低,与circRNA-Tbpl1呈负相关。与sh-NC组相比,sh-circRNA-Tbpl1组的自噬水平减弱,细胞增殖活力降低。与sh-circRNA-Tbpl1 + miRNA-NC组相比,sh-circRNA-Tbpl1 + miR-214-3p抑制物组的自噬水平升高,细胞增殖活力增强。结论 circRNA-Tbpl1通过海绵吸附miR-214-3p抑制低氧诱导的自噬,从而缓解低氧性肺动脉高压血管重塑。     

心肌酶谱和血清肌钙蛋白测定在新生儿缺氧性肺动脉高压诊断中的应用

目的：探讨心肌酶谱和血清肌钙蛋白测定在新生儿缺氧性肺动脉高压（HPH）中的诊断价值。方法：HPH患儿作为实验组,并与同期入院的非缺氧和心肌损害患儿作为对照组,每组各30例,分别于出生后第1d和第7d检测两组患儿心肌酶谱和血清肌钙蛋白（cTnI）,自动血气分析仪测定氧分压（Pa02）,三尖辨返流压差法测定肺动脉收缩压（PASP）,比较两组患儿心肌酶谱、cTnI与PaO2及PASP之间的关系。结果：第1d时实验组LDH、CK、CK-MB、a-HBDH、cTnI均显著高于对照组（P〈0．01）;出生后第1d实验组PASP显著低于对照组,PaO：显著高于对照组（P〈0．01）,第1d时实验组PaO与CK-MB、cTnI呈明显负相关（P〈0．05）。结论：CK-MB和cTnl与PASP呈明显正相关,与Pa02呈明显负相关,可作为早期诊断HPH的特异性指标之一。     

Workplace violence against nurses – Prevalence and association with hospital organizational characteristics and health-promotion efforts: Cross-sectional study

Purpose/objectivesTo determine the prevalence of workplace violence and explore the role of hospital organizational characteristics and health promotion efforts in reducing hospital violence among nurses in Taiwan.DesignCross-sectional survey.SettingOne hundred hospitals across Taiwan.SampleThe final sample in our study comprised responses from 26,979 nurses.MethodsThe data were obtained from a nationwide hospital survey, Physical and Mental Health and Safety Needs in Full-Time Health Care Staff, which was developed and conducted by the Bureau of Health Promotion, Taiwan, in 2011.Main research variablesThe main dependent variable was whether nurses had experienced violence within the past year. Physical violence, threatened or intimidated personal safety, verbal violence or sexual harassment were all included.FindingsOf the 26,979 nurses, 13,392 nurses (49.6%) had experienced at least one episode of any type of violence in the past year; 5150 nurses (19.1%) had been exposed to physical violence, and 12,491 nurses (46.3%) had been exposed to non-physical violence. The prevalence of having experienced any violence varied widely and ranged from the highest (55.5%) in an emergency room or intensive care unit to the lowest (28.3%) among those aged 55–65 years. After adjusting for other characteristics, younger nurses were significantly more likely to be exposed to any violent threat. Nurses working in public hospitals had a significantly higher risk of workplace violence than those working in private hospitals. Significant variations were also observed among work units. Although nurses working in a certified health promoting hospital (HPH) did not have a lower risk of workplace violence, those working in an outstanding HPH had a significantly lower risk of workplace violence. A similar pattern was observed for non-physical violence.ConclusionsWorkplace violence is a major challenge to workplace safety for nurses in hospitals. This large scale nurse survey identified individual, work and hospital characteristics associated with workplace violence among hospital nurses. Preventive efforts in reducing hospital violence shall be targeted these high risk groups and settings.Implications for nursingThis nationwide nurse survey assisted us in more clearly understanding the scope of the hospital violence facing nurses and identifying critical risk factors. The findings not only identified the most common locations of violence in hospitals but also suggested that extensive investments and efforts by hospitals in health promotion are crucial.     

缺氧性肺血管构型重建的中医认识

本文认为,缺氧性肺血管构型重建是低氧性肺动脉高压持续发展的主要病理基础,通过对临床和病理改变的分析,提出形成肺血管构型重建的中医病因病机为:气虚是始动因素,又是基本病机,是肺气虚向肺肾气虚的演变,血瘀、痰阻是继发的病理改变,肺络不通是局部的病理结果;治疗应以补益肺肾、活血消痰、疏通肺络为基本原则。