Tissue renin-angiotensin systems and reproduction

The continued acquisition of information on the distribution of expression of components of the renin-angiotensin system shows that it has functions in the tissues that are quite unrelated to its systemic actions. In particular, both type 1 and type 2 angiotensin receptors are found in many tissues of the reproductive system of both sexes. In addition, the widespread occurrence of (pro)renin, angiotensin converting enzyme and angiotensinogen suggests that the generation of angiotensin II within the tissues occurs at sites close to its sites of action. The data suggest that angiotensin II operates as an important paracrine agent with profoundly significant roles in several functions of the reproductive system, and in fertility.      

Poxvirus immune modulators: functional insights from animal models

Poxviruses express several different classes of immune modulators that suppress the host response to infection, including soluble cytokine binding proteins, serpins, chemokine binding proteins, a complement control protein, and members of the semaphorin and Toll/IL-1 receptor families. Biochemical activity of these proteins has been demonstrated by many in vitro studies. Conservation in evolution of poxvirus immune modulators implies that these genes are functional in vivo, but the results of infecting animals with knockout viruses have not always been clear cut. Studies involving different animal models are reviewed, and the criteria for suitable models are discussed. Challenges include finding an appropriate animal host, and using an inoculation route that resembles the process of natural infection. The fact that multiple immune modulators can target the same pathway at different steps may explain why single knockout mutants are not always attenuated in animals.     

The mechanisms of coronary restenosis: insights from experimental models

Since its introduction into clinical practice, more than 20 years ago, percutaneous transluminal coronary angioplasty (PTCA) has proven to be an effective, minimally invasive alternative to coronary artery bypass grafting (CABG). During this time there have been great improvements in the design of balloon catheters, operative procedures and adjuvant drug therapy, and this has resulted in low rates of primary failure and short-term complications. However, the potential benefits of angioplasty are diminished by the high rate of recurrent disease. Up to 40% of patients undergoing angioplasty develop clinically significant restenosis within a year of the procedure. Although the deployment of endovascular stents at the time of angioplasty improves the short-term outcome, 'in-stent' stenosis remains an enduring problem. In order to gain an insight into the mechanisms of restenosis, several experimental models of angioplasty have been developed. These have been used together with the tools provided by recent advances in molecular biology and catheter design to investigate restenosis in detail. It is now possible to deliver highly specific molecular antagonists, such as antisense gene sequences, to the site of injury. The knowledge provided by these studies may ultimately lead to novel forms of intervention. The present review is a synopsis of our current understanding of the pathological mechanisms of restenosis.     

Advances in sepsis research derived from animal models

Inflammation is the basic process by which tissues of the body respond to infection. Activation of the immune system normally leads to removal of microbial pathogens, and after resolution of the inflammation immune homeostasis is restored. This controlled process, however, can be disturbed resulting in disease. Therefore, many studies using infection models have investigated the participating immune mechanisms aiming at possible therapeutic interventions. Defined model substances such as bacterial lipopolysaccharide (endotoxin) have been used to mimic bacterial infections and analyze their immune stimulating functions. A complex network of molecular mechanisms involved in the recognition and activation processes of bacterial infections and their regulation has developed from these studies. More complex infection models will now help to interpret earlier observations leading to the design of relevant new infection models.     

Tissue oxygenation in sepsis; new insights from in vivo EPR

Nitric oxide (NO) is a key mediator in the maldistribution of oxygen by tissue and organ dysfunction observed in sepsis. Despite this, few techniques are capable of measuring these parameters directly in vivo. We describe here several techniques that have been developed by our group to address this directly by in vivo EPR in animal models of sepsis. Oxygen-sensitive materials can be implanted or administered and report on local tissue pO2. Spin trapping of NO can simultaneously report on tissue NO content. Repeat measures of these parameters can be made directly from a defined tissue site, allowing development of new models and experiments to study the defects in tissue and organ function seen in sepsis.     

Neutrophils: Critical components in experimental animal models of cancer

Neutrophils have a crucial role in tumor development and metastatic progression. The contribution of neutrophils in tumor development is multifaceted and contradictory. On the one hand, neutrophils prompt tumor inception, promote tumor development by mediating the initial angiogenic switch and facilitate colonization of circulating tumor cells, and on the other hand, have cytotoxic and anti-metastatic capabilities.Our understanding of the role of neutrophils in tumor development has greatly depended on different experimental animal models of cancer. In this review we cover important findings that have been made about neutrophils in experimental animal models of cancer, point to their advantages and limitations, and discuss novel techniques that can be used to expand our knowledge of how neutrophils influence tumor progression.     

Deepen the understanding and communication of animal models and experimental medicine research studies

At the first issue of the year 2021, I would like to extend my sincere gratitude for your continued support and attention to Animal Models and Experimental Medi...     

Transgenic animal models: new avenues in cardiovascular physiology

 Application of molecular genetic tools to inherited cardiovascular disorders has provided important insights into the molecular mechanisms underlying cardiomyopathies, arrhythmias, blood pressure regulation, and atherosclerosis. In addition, alteration of gene expression has been observed under common cardiovascular conditions such as cardiac hypertrophy and heart failure. Recent advances in transgenic and gene-targeting approaches allow a sophisticated manipulation of the mouse genome by gene addition, gene deletion, or gene modifications. These transgenic models enable the dissection of in vivo pathways responsible for these complex disease phenotypes. This review describes tissue-specific promoters suitable for targeting candidate genes to the cardiovascular system as well as a number of valuable transgenic animal models of blood pressure regulation, atherogenesis, defects in the coagulation system, cardiac hypertrophy, myocarditis, cardiomyopathies, and heart failure. Limitations and difficulties associated with these transgenic approaches are discussed. Animal models which may provide a basis for future gene therapy of cardiovascular diseases are introduced. Finally, methods are described to regulate the spatial and temporal expression level of a transgene, to inactivate a target gene in a tissue-specific manner, and to introduce specific mutations into the genome. These recent advances in transgenic technology are expected to have a considerable impact on cardiovascular research in the near future. Received: 1 February 1996 / Accepted: 13 August 1996     

Selection in a T-dependent primary humoral response: new insights from polypeptide models.

Regulatory mechanisms involved in the induction and progression of T-dependent humoral responses have been extensively delineated using a variety of haptens as model antigens. However, several unanswered questions remain with respect to those elicited by structurally more complex molecules. Our own laboratory has been pursuing this latter aspect using designed synthetic peptides as model systems. The cumulative results indeed support that humoral responses to such antigens involve several additional layers of regulation, beyond that identified with haptens. At the first level, the multiplicity of antigenic determinants recognized by the preimmune B-cell pool is soon subject to competitive pressures that restrict, both at the level of repertoire and epitope, fine specificities of early activated clonotypes. Selection at this stage is on the basis of affinity for epitope, which, in turn, is under thermodynamic control. This selected B-cell subset proceeds to populate germinal centers, where further optimization--by way of somatic hypermutation followed by clonal selection--is in favor of increased on-rates of antigen binding. Thus, contrary to findings with hapten antigens, maturation of antibody responses to polypeptides occurs in two discrete, but sequential, stages. The first is for B cells with optimum affinity for the corresponding epitope. This is then followed by further improvement on the basis of increased on-rates of antigen/epitope binding. It is a combination of these two processes which results in the high fidelity of antibodies produced in the secondary response.     

Innovations in osteomyelitis research: A review of animal models

Infection of bone tissue, or osteomyelitis, has become a growing concern in modern healthcare due in no small part to a rise in antibiotic resistance among bacteria, notably Staphylococcus aureus. The current standard of care involves aggressive, prolonged antibiotic therapy combined with surgical debridement of infected tissues. While this treatment may be sufficient for resolving a portion of cases, recurrences of the infection and associated risks including toxicity with long‐term antibiotic usage have been reported. Therefore, there exists a need to produce safer, more efficacious options of treatment for osteomyelitis. In order to test treatment regimens, animal models that closely mimic the clinical condition and allow for accurate evaluation of therapeutics are necessary. Establishing a model that replicates features of osteomyelitis in humans continues to be a challenge to scientists, as there are many variables involved, including choosing an appropriate species and method to establish infection. This review addresses the refinement of animal models of osteomyelitis to reflect the clinical disease and test prospective therapeutics. The aim of this review is to explore studies regarding the use of animals for osteomyelitis therapeutics research and encourage further development of such animal models for the translation of results from the animal experiment to human medicine.     

实验性变态反应性脑脊髓炎模型研究进展

实验性变态反应性脑脊髓炎（EAE）动物模型是研究人类多发性硬化（MS）的理想动物模型,在神经免疫性疾病研究中具有重要意义。了解EAE模型（被动免疫模型和主动免疫模型）制备的有关问题,包括实验动物的品系、性别、年龄的选择,抗原的选择,佐剂的选择,免疫方法的选择,模型的制作,动物临床发病过程,病情评分等及其在研究多发性硬化的发病机制、炎症反应和临床前药物试验等研究中的应用,以及存在的局限性具有重要意义。     

Natural killer cell differentiation: insights from knockout and transgenic mouse models and in vitro systems

Summary: In the last few years, the routine development of knockout and transgenic mice and the ease with which rare progenitor populations can be isolated from hematopoietic organs and cultured in vitro has facilitated significant advances in understanding the lineage and development of natural killer (NK) cells. Fluorescence-activated cell sorter analyses have identified a common lymphoid progenitor capable of giving rise to NK, T, and B cells, confirming the lymphoid origin of NK cells. Knockout and transgenic mouse models have pointed to an absolutely critical role for signals sent through the interleukin (IL)-2/lS receptor β (CD 122) chain and common γ (γc) chain for NK development. Such signals are likely relayed inside the cell by the tyrosine kinase Jak3, which associates with γc. Recently developed IL-15 and IL-15 receptor a knockout mice have pinpointed IL-15 as the mediator of this signal. Other mouse models have indicated an unexpected role for flt3 ligand in early NK-cell development as well as minor roles for stem cell factor and IL-7 in expanding NK-cell progenitor numbers. Finally, in vitro culture systems have proven useful in identifying the point in NK development at which each of these signals is critical.     

Crossing the bridge: large animal models in translational transplantation research

Summary:  Many methods for reducing the immunosuppressive requirements of allotransplantation have been proposed based on a growing understanding of physiological and allospecific immunity. As these regimens are developed for clinical application, they require validation in models that are reasonably predictive of their performance in humans. This article provides an overview of the large animal models commonly used to test immunomodulatory organ transplant protocols. The rationale for the use of large animals and the effects of common immunosuppressants in the dog, pig, and non-human primate are reviewed. Promising methods for the induction of allospecific tolerance are surveyed with references to early human trials where appropriate.     

Evaluation of quinolones in experimental animal models of infections

Many discriminative experimental animal models of infection have been utilized in the evaluation of newer fluoroquinolones. In vivo efficacy of many of the newer agents has been shown in experimental models of meningitis, endocarditis, pneumonia, urinary tract infections, pyelonephritis, osteomyelitis, abscesses of various types, septic arthritis, gastroenteritis, salmonellosis, listeriosis, tuberculosis, syphilis, sinusitis, prostatitis and burn wound sepsis, among others. This review focuses on recent developments in a few selected areas. Although the limitations of animal model studies are well described, these results provide a rationale for the appropriate clinical usage of the newer fluoroquinolones in humans.     

Neuroinvasion of prions: insights from mouse models

The prion was defined by Stanley B. Prusiner as the infectious agent that causes transmissible spongiform encephalopathies. A pathological protein accumulating in the brain of scrapie-infected hamsters was isolated in 1982 and termed prion protein (PrPSc). Its cognate gene Prnp was identified more than a decade ago by Charles Weissmann, and shown to encode the host protein PrP(C). Since the latter discovery, transgenic mice have contributed many important insights into the field of prion biology, including the understanding of the molecular basis of the species barrier for prions. By disrupting the Prnp gene, it was shown that an organism that lacks PrP(C) is resistant to infection by prions. Introduction of mutant PrP genes into PrP-deficient mice was used to investigate the structure-activity relationship of the PrP gene with regard to scrapie susceptibility. Ectopic expression of PrP in PrP knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrP knockout mice and transgenic mice overexpressing PrP allows selective reconstitution experiments aimed at expressing PrP in neurografts or in specific populations of haemato- and lymphopoietic cells. The latter studies have allowed us to clarify some of the mechanisms of prion spread and disease pathogenesis.     

Update on animal models for HIV research

Animal models for HIV research have been indispensible in fulfilling Koch's postulate and in exploring issues of viral infectivity and pathogenesis, sequence divergence, route(s) of acquisition, tissue distribution and tropism, immunogenicity and protection capacity of vaccine candidates, escape from adaptive immunity, and more. Did they fail to predict the efficacy of T‐cell vaccines in humans? This article summarizes progress and status of models to inform and complement clinical work.     

实验性抑郁症动物模型的评价

抑郁属于情感障碍性疾病 ,其发病率逐年增加 ,对人类的健康和生命已构成威胁 ,并引起了人们广泛的重视。关于抑郁的发病机理和药物治疗 ,通过实验研究 ,人们提出了中枢递质假说 ,认为脑内单胺类递质功能紊乱与抑郁发病有关 ,并建立了相应的动物模型 ,进行抗抑郁药物的广泛研究。然而 ,在对该类动物模型进行评价中 ,遇到了几个难以解释的问题 :其一是抗抑郁药急性处理有效 ,而临床抑郁病人症状改善需用药治疗 1- 3周 ,在作用时程上不相吻合 ;其二是增加脑内突触间隙单胺类递质功能的药物 ,临床上并无抗抑郁作用 ;其三是对脑内单胺类递质代谢…