子痫前期动物模型的研究进展

子痫前期是一种非常严重的妊娠疾病,主要症状有高血压、蛋白尿、内皮功能障碍、肾小球血管内皮细胞增生以及滋养层细胞浸润不足等,动物模型是研究本病发病机理与开发诊治手段的主要工具.长期以来,针对子痫前期主要症状已经建立了多种动物模型,但不同的动物模型各有优缺点,至今仍没有一个理想的子痫前期动物模型,这也是子痫前期病因不明和缺乏有效治疗手段的主要原因之一.本文就已有的模型进行了归纳总结,旨在为不同研究需要而选择合适的模型,并为开发更为理想的子痫前期动物模型提供参考.     

Animal models of portal hypertension

Chronic liver diseases ultimately lead to cirrhosis and portal hypertension (PHT). Indeed, PHT is a major cause of severe complications, while medical treatment is limited to non-selective beta blockers. Sophisticated animal models are needed to investigate novel treatment options for different etiologies of liver disease, effective anti-fibrotic agents as well as vasoactive drugs against PHT. In this review, we present some of the most common animal models of liver disease and PHT – including pre-hepatic, intra-hepatic and post-hepatic PHT in rodents. Methodology for induction, considerations for disease etiology, advantages and limitations and practical issues of these animal models are discussed. The appropriate and sensible use of animal models in preclinical research supporting the 3R concept of replacement, reduction and refinement is highlighted.     

A role of calcium in altered sodium ion transport of hypertensives?

Research on the etiology of essential hypertension has led to many reports of altered ion transport in cells from hypertensive patients and animal models. Abnormalities in sodium and calcium ion gradients and transport in vascular smooth muscle, neuronal tissue, cardiac muscle as well as erythrocytes have been extensively investigated. It is not clear whether these abnormalities are of primary or secondary nature. The current knowledge of sodium and calcium ion transport in essential hypertension is briefly reviewed here. Furthermore, evidence is presented which suggests a role of calcium in the regulation of sodium transport activity.     

Linking animal models to human congenital diaphragmatic hernia

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a major life-threatening malformation, occurring in approximately 1 in 3,000 live births. Over the years, different animal models have been used to gain insight into the etiology of this complex congenital anomaly and to develop treatment strategies. However, to date the pathogenic mechanism is still not understood, and treatment remains difficult because of the associated pulmonary hypoplasia and pulmonary hypertension. METHODS: In this review, data available from several animal models will be discussed. The retinoic acid signaling pathway (RA pathway, retinoid pathway) will be addressed as a developmental pathway that is potentially disrupted in the pathogenesis of CDH. Furthermore, genetic factors involved in diaphragm and lung development will be discussed. CONCLUSIONS: With this review article, we aim to provide a concise overview of the current most important experimental genetic data available in the field of CDH.     

转基因肺癌动物模型研究进展

肺癌是世界各国常见的恶性肿瘤,肺癌动物模型在人类肺癌病因、诊断、治疗等方面发挥重要的作用。其中转基因肺癌模型能够更好的模拟肺癌,更有利于肺癌病因及发病过程的研究。本文介绍了近年来转基因肺癌模型的研究进展。     

Neural tube defects: a review of human and animal studies on the etiology of neural tube defects

Although neural tube defects are a common congenital anomaly, their etiology is not known. Human studies have emphasized the pathology and epidemiology of the defects and suggest that in the majority of cases the etiology is multifactorial. Factors which appear possibly to be important are genetic predisposition, maternal illness, and fetal drug exposure. Animal studies have utilized naturally occurring neural tube defects and teratologically induced lesions. No animal model has been convincingly established as the equivalent of human neural tube defects. However, animal models have allowed investigation of the mechanisms of suggested human teratogens and determination of the pathogenesis of naturally occurring animal defects. Their most important contribution has been in furthering the understanding of the normal mechanisms of neural tube closure. It may be through this understanding that the etiology of human neural tube defects will be determined.     

Pathophysiology of hypertension in response to placental ischemia during pregnancy: A central role for endothelin?

Background: Preeclampsia is new-onset hypertension with proteinuria during pregnancy. The initiating event in preeclampsia has been postulated to involve reduced placental perfusion, which leads to widespread dysfunction of the maternal vascular endothelium.Objective: The main objective of this brief review was to highlight some of the recent advances in our understanding of the mechanisms whereby the endothelin (ET) system, via ET type A (ET_A) receptor activation, modulates blood pressure in preeclamptic women and in animal models of pregnancy-related hypertension.Methods: This review focused on the role of ET and tumor necrosis factor-α (TNF-α) in preeclampsia, with emphasis on the pathophysiology of hypertension in response to placental ischemia in animal models of pregnancy. Relevant published data were identified by searching PubMed and supplemented with contributions from our laboratory.Results: Studies in preeclamptic women indicate that their hypertension is associated with increases in ET synthesis. Recent studies in pregnant rats indicate that the ET system is activated in response to reductions in uterine perfusion pressure and to chronic elevations in serum TNF-α concentrations. In these 2 animal models, the findings also suggest that ET A receptor activation may play a role in mediating hypertension.Conclusions: Although recent studies in animal models implicate an important role for the ET system in preeclampsia, the usefulness of selective ET A receptor antagonists for the treatment of hypertension in women with preeclampsia remains unclear. This important question will not be answered until well-controlled clinical studies using specific ET A receptor antagonists are conducted for women with preeclampsia.     

Antihypertensive effects of vanadium compounds in hyperinsulinemic,hypertensive rats

Although considerable evidence lends credence to the association between insulin resistance, hyperinsulinemia and essential hypertension, the precise nature of this relationship remains unexplained. In the present investigation, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. If these metabolic abnormalities were responsible for the development of hypertension, then drug interventions that improve these defects should also decrease high blood pressure. Since previous studies have demonstrated that vanadium compounds enhance insulin action and lower plasma insulin levels in nondiabetic rats, we examined the effects of these compounds on insulin sensitivity, plasma insulin concentration and blood pressure in two hyperinsulinemic models of experimental hypertension. The animal models studied were the genetically predisposed spontaneously hypertensive rat and the fructose-hypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. Vanadium compounds caused marked and sustained decreases in plasma insulin concentration and blood pressure in both the animal models studied. Furthermore, the effect of the drugs on blood pressure was reversed by restoring plasma insulin levels in the drug-treated rats to those observed in their untreated counterparts. These data suggest that either hyperinsulinemia contributes to the development of hypertension in both the spontaneously hypertensive and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.     

两种高血压大鼠模型证候特征差异性的研究

目的探讨两种经典高血压实验动物模型的证候特征,以便更好地考察降压中药疗效及作用机理。方法选择自发性高血压大鼠和肾性高血压大鼠两种经典常用动物模型,从宏观表征和行为学的角度,对二者的证候特征及其差异性进行辨析比较。结果自发性高血压大鼠在14～18周龄,基本符合高血压中医辨证分型中肝火上炎证型的表现;两肾一夹型肾性高血压大鼠在术后4～8周,基本符合高血压中医辨证分型中阴虚阳亢证型的表现。结论两种高血压动物模型的中医证候特征不同,在进行降压中药的疗效评价和作用机理实验研究时,可以考虑有针对性地选用。     

Animal models of sudden unexplained death

The etiology of sudden infant death syndrome (SIDS) is unknown but thought to be multifactorial. Several animal models have been developed that induce death without pre-existing symptoms and with pathology similar to that seen in SIDS infants; however, the relevance of these animal models to the events leading to SIDS remains elusive, in part because animal models are as varied as the potential causes of SIDS. In addition, it is difficult to find an animal model that can accurately reflect the genetic, developmental and environmental risk factors for SIDS. Comparisons between species can prove difficult but animal models provide a useful tool for evaluating potential mechanisms related to sudden unexplained death. This review focuses on models developed to examine the association of infection and inflammation with mechanisms proposed to explain sudden unexplained death.     

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD)

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.     

Human genetics, animal models and computer simulations for studying hypertension

Essential hypertension is probably caused by combinations of small quantitative changes in the expression of many genes together with environmental factors. In this article, strategies for studying hypertension using animal models are summarized with emphasis on the combined use of mouse models and computer simulations. We have chosen the rennin-angiotensin system as our main example. Future directions of hypertension research using gene targeting are also discussed.     

阿尔兹海默症转基因小鼠模型研究进展及评价

随着世界人口的老龄化,阿尔兹海默症已经成为严重威胁老年人健康的主要疾病之一,研究并建立可靠的阿尔兹海默症动物模型对于探明疾病的病因、发病机制及防治药物的开发均具有重要意义。本文就目前使用最为广泛和研究最为深入的转基因小鼠模型的病理、行为学变化特点及其在阿尔兹海默症研究中的应用和发现作一介绍。     

泌尿道感染动物模型制作研究现状

建立与人类泌尿道感染相似的可靠动物模型,对探讨泌尿道感染发病机制和研究治疗方法十分必要。本文介绍了急性肾盂肾炎,慢性肾盂肾炎,腺性膀胱炎等泌尿道感染模型制作研究现状,并从菌种,品系等角度进行探讨。     

The Orexin System and Hypertension

In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar–Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.     

Animal models of pulmonary hypertension: Rho kinase inhibition

Pulmonary Hypertension is a terminology encompassing a range of etiologically different pulmonary vascular diseases. The most common is that termed pulmonary arterial hypertension or PAH; a rare but often fatal disease characterized by a mean pulmonary arterial pressure of >25?mmHg. PAH is associated with a complex etiology highlighted by core characteristics of increased pulmonary vascular resistance and elevation of mean pulmonary artery pressure. When sustained, pulmonary vascular remodeling occurs and eventually patients pass away due to right heart failure. Hypoxic pulmonary vasoconstriction is an early event occurring in pulmonary hypertension due to chronic exposure to hypoxia. While the underlying mechanisms of hypoxic pulmonary vasoconstriction may be controversial, a role for RhoA/Rho kinase mediated regulation of intracellular Ca(2+) has been recently identified. Further study suggests that RhoA may have an integral role in other pathophysiological processes such as cell proliferation and migration occurring in all forms of PH. Indeed Rho proteins are known to play essential roles in actin cytoskeleton organization in all eukaryotic cells and thus Rho and Rho-GTPases are implicated in fundamental cellular processes such as cellular proliferation, migration, adhesion, apoptosis and gene expression. This review focuses on providing an overview of the role of RhoA/Rho kinase in currently available animal models of pulmonary hypertension.     

Reproducibility in animal models of hypertension: a difficult problem

In 2016, the National Institutes of Health mandated that all grant proposals enhance reproducibility through rigor and transparency. In the past few years, physiological outcomes in established animal models of hypertension, in particular in regard to sex differences, have varied from study to study or laboratory to laboratory. The aim of this commentary is to increase investigator awareness of caveats related to animal models that may be sensitive to vendor-, barrier-, or diet-specific changes that result in an inability to sustain the genotype and/or phenotype of well-established experimental models. These considerations are critical in order for investigators to make informed and educated decisions in regard to their hypothesis-driven research, in particular as it relates to experimental design and interpretation, and the reporting of results.     

阿尔茨海默病转基因小鼠的特点和应用

建立动物模型的目的是在实验动物身上复制人类疾病的模型,用于研究人类疾病的病因、发病、病理变化以及疾病的预防和治疗。目前尚无理想的阿尔茨海默病（Alzheimer’s disease,AD）动物模型,AD实验动物模型的滞后在很大程度上制约了AD治疗药物的筛选。随着AD病因和发病机制研究的不断深入,更完善的AD动物模型也在陆续出现。近年来出现的转基因动物模型属于AD的病因模型,但也不能完整复制出AD的所有特征。最大的缺憾在于缺乏神经原纤维缠结（neurofibrillary tangles,NFTs）和在某些转基因模型中（尤其是单转基因模型）无广泛的神经元丢失。虽然用免疫组化方法检测到tau蛋白,但从未发现成对螺旋纤丝（paired helical filaments,PHF）。     

Fetal programming of hypertension

Numerous epidemiological studies suggest an inverse relationship between low birth weight (LBW) and hypertension, an observation now supported by numerous animal studies. The mechanisms linking LBW and hypertension appear to be multifactorial and involve alterations in the normal regulatory systems and renal functions involved in the long-term control of arterial pressure. Recent studies using animal models of fetal programming suggest that programming during fetal life occurs in response to an adverse fetal environment and results in permanent adaptive responses that lead to structural and physiological alterations and the subsequent development of hypertension. This review summarizes the adaptive responses observed in the different models used to induce a suboptimal fetal environment and discusses insights into the mechanisms mediating the fetal programming of hypertension.