Pathophysiology of saphenous vein graft failure: a brief overview of interventions

Coronary artery bypass graft surgery (CABG) is widely used for the treatment of atheromatous stenosis of coronary arteries. However, as many as 50% of grafts fail within 10 years after CABG due to neointima (NI) formation, a process involving the proliferation of vascular smooth muscle cells (VSMCs) and superimposed atherogenesis. To date no therapeutic intervention has proved successful in treating late vein graft failure. However, several diverse approaches aimed at preventing neointimal formation have been devised which have yielded promising results. In this review, therefore, we will summarise the pathophysiology of vein graft disease and then briefly consider interventional approaches to prevent late vein graft failure which include surgical technique, conventional pharmacology, external sheaths, cytostatic drugs and gene transfer.     

Animal models of central nervous system immune-mediated diseases: therapeutic interventions with bioactive peptides and mimetics

Experimental allergic encephalomyelitis (EAE) is a T helper 1 (Th1) mediated autoimmune disease and the principal animal model for multiple sclerosis (MS). Like MS, EAE is characterized by a coordinated inflammatory attack on the myelin sheath in the central nervous system (CNS), with damage to axons. No matter whether the ideal animal model is not yet available, much knowledge concerning the pathogenesis of MS has been achieved through studies on EAE. Dissecting the underlying immune mechanisms provided recognition of several myelin antigens that are vulnerable in autoimmune attack. The beneficial effect and the mechanism of action of a number of the currently used immunomodulating agents in MS therapy were first indicated in EAE. Altered peptide ligands (APL) can modulate T-cell responses to native peptide antigens implicated in the pathogenesis of autoimmune diseases such as MS and EAE. However, peptide therapy is hindered due to the sensitivity of peptides to proteolytic enzymes as well as due to some immune-mediated side effects. A number of cyclic myelin peptide analogs seem to be potential candidates in maintaining the biological function of the original peptide and effective in controlling inflammation in EAE. Additional data regarding the immunomodulating and neuroprotective effect of these much promising agents is required. Based on the data from studies on EAE models, clinical trials should also be designed in order to elucidate the impact of such APL-induced immune responses in MS disease activity. These clinical trials should carefully incorporate monitoring of both clinical, neuroimaging and immunological parameters.     

Nootropic drugs: Animal models for studying effects on cognition

The term “nootropic” refers to compounds that act on cognitive functions. These drugs should facilitate learning and memory and prevent impairment of cognitive functions induced by diseases and brain insults. In animal models of impaired cognitive functions, the effects of several nootropic substances were investigated. Learning and retention in passive avoidance, and positive reinforcement paradigms were disrupted by hypoxia, cerebral ischemia and amnesia-inducing agents. Piracetam and several other novel nootropic compounds were shown to improve performance in these animal models. These results indicate that experimentally induced cognitive dysfunction in animals can be attenuated with drug treatment.     

Animal models of acute renal failure

The animal models are pivotal for understanding the characteristics of acute renal failure (ARF) and development of effective therapy for its optimal management. Since the etiology for induction of renal failure is multifold, therefore, a large number of animal models have been developed to mimic the clinical conditions of renal failure. Glycerol-induced renal failure closely mimics the rhabdomyolysis; ischemia-reperfusion-induced ARF simulate the hemodynamic changes-induced changes in renal functioning; drug-induced such as gentamicin, cisplatin, NSAID, ifosfamide-induced ARF mimics the renal failure due to clinical administration of respective drugs; uranium, potassium dichromate-induced ARF mimics the occupational hazard; S-(1,2-dichlorovinyl)-L-cysteine-induced ARF simulate contaminated water-induced renal dysfunction; sepsis-induced ARF mimics the infection-induced renal failure and radiocontrast-induced ARF mimics renal failure in patients during use of radiocontrast media at the time of cardiac catheterization. Since each animal model has been created with specific methodology, therefore, it is essential to describe the model in detail and consequently interpret the results in the context of a specific model.     

Statins and vein graft failure in coronary bypass surgery

Saphenous vein grafts used in coronary artery bypass graft surgery suffer from lower patency rates compared to left internal mammary artery. A number of clinical trials and observational studies have demonstrated a significant benefit of statin treatment on vein graft patency. Aside from their well-known lipid-lowering capacities, statins exert pleiotropic effects by direct inhibition of the mevalonate pathway in the wall of these grafts. This leads to reduced geranylgeranylation of small GTPases such as Rho and Rac. Through this LDL-independent mechanism, statins improve endothelial function and reduce vascular inflammation and oxidative stress, inhibiting also smooth muscle cell proliferation and migration. Although the existing evidence supports a beneficial effect of statins on vein grafts biology, more clinical trials focused on the effect of aggressive statin treatment on vein graft patency are required, in order to safely translate this strategy into clinical practice.     

Endothelin-1 (ET-1) and vein graft failure and the therapeutic potential of ET-1 receptor antagonists

Despite the exploration of a large number of disparate drugs in animal models and clinical trials, no pharmacological intervention, with the exception of aggressive lipid lowering therapy has reduced late vein graft failure in man. The importance of devising more effective strategies is exemplified by the enormous economic consequences of vein graft failure. Worldwide, there are currently more than 1,000,000 coronary artery bypass graft surgery (CABG) operations a year, the same number of patients undergoing infrainguinal bypass for vascular diseases of the lower limb. The pathophysiology of vein graft failure is complex, involving disparate factors that include adhesion of platelets and leukocytes, rheological forces, metalloproteinase expression, proliferation and migration of vascular smooth muscle cells, neointima formation, oxidative stress, hypoxia and neural re-organisation. Although this diverse etiology may seem to preclude any single drug type as being effective in mediating vein graft failure: one factor that is involved in every facet of vein graft pathobiology is endothelin-1 (ET-1). As such a single drug type (ET_A antagonist) may prove to be the magic bullet in this scenario. Thus, in this review, we will consider the etiology of vein graft disease in relation to ET-1 and will then present an argument (with evidence) that specific ET_A receptor antagonists constitute a potentially effective means of preventing vein graft failure.     

Animal and human models for studying effects of drugs on intestinal fluid transport in vivo

The understanding of the physiology and pathophysiology of intestinal fluid transport has been derived from animal and human models of normal and perturbed intestines. This understanding helped in designing drugs and changing the composition of oral rehydration solutions in a targeted manner to affect intestinal fluid absorption/secretion that was tested both in vitro and in vivo before embarking on clinical trials. In this review, in vivo techniques used to study water transport in both animal and human models are described. In particular, steady state intestinal perfusion techniques, closed segment techniques, fistulous animal models, balance study models, enteropooling models, and isotope tracer models are reviewed. Advantages and drawbacks of each technique and examples where drug effects have been studied in a particular model are provided.     

Surgical trauma and vein graft failure: further evidence for a role of ET-1 in graft occlusion

The saphenous vein (SV) is the most commonly used conduit for coronary artery bypass surgery. However, using traditional techniques, the occlusion rate for the SV is high, with over 50% of grafts failing within 10 years. In conventional coronary artery bypass surgery the SV is exposed to considerable damage during preparation for grafting. Recently, an increased graft patency has been described using a 'no-touch' technique, whereby the vein is prepared with minimal vascular trauma. There is evidence that the success of this form of coronary artery bypass surgery is a result, at least in part, of the retention of tissue-derived nitric oxide. We have examined the effects of conventional SV harvesting on vessel morphology, cell proliferation, endothelin-1 and its receptors. Considerable damage was observed in veins prepared using conventional surgery compared to 'no-touch' veins. The vessel wall exhibited evidence of surgical trauma, with regions of denudation of the luminal endothelium caused by distension. Endothelin-1 and endothelin-A receptors were present at subintimal regions of conventional SV segments where proliferating cells were identified. Endothelial endothelin-B receptors were also revealed that were absent at areas of distension-induced damage to the endothelium. These results suggest that endothelin-1 plays a role in vein graft failure, predominantly via the endothelin-A receptor.     

Animal models of asthma: potential usefulness for studying health effects of inhaled particles

Asthma is now recognized to be a chronic inflammatory disease that affects the whole lung. Incidence appears to be increasing despite improved treatment regimens. There is substantial epidemiological evidence suggesting a relationship between the incidence and severity of asthma (e.g., hospitalizations) and exposure to increased levels of air pollution, especially fine and ultrafine particulate material, in susceptible individuals. There have been a few studies in animal models that support this concept, but additional animal studies to test this hypothesis are needed. However, such studies must be performed with awareness of the strengths and weaknesses of the currently available animal models. For studies in mice, the most commonly used animal, a broad spectrum of molecular and immunological tools is available, particularly to study the balance between Th1 and Th2 responses, and inbred strains may be useful for genetic dissection of susceptibility to the disease. However, the mouse is a poor model for bronchoconstriction or localized immune responses that characterize the human disease. In contrast, allergic lung diseases in dogs and cats may more accurately model the human condition, but fewer tools are available for characterization of the mechanisms. Finally, economic issues as well as reagent availability limit the utility of horses, sheep, and primates.     

Animal models of cardiac disease: potential usefulness for studying health effects of inhaled particles

Cardiac disease is one of the major causes of morbidity and mortality worldwide and is the leading cause of death in the United States. Epidemiologic studies have shown a close association between morbidity and mortality from cardiac disease, primarily in persons already affected, and with modest increases in levels of air pollution. At present, no mechanisms are known by which inhaled air pollutants interact with the heart to cause death. Thus, animal models of cardiac disease are needed to study possible interactions between inhaled pollutants and the heart and the resultant morbidity and mortality. Very little research in animals has been conducted in this area, and appropriate animal models must be carefully selected. The purpose of this review is to examine several potential animal models and to discuss their advantages and disadvantages in the study of cardiac disease and air pollution.     

Novel therapeutic interventions for allergic rhinitis

Allergic rhinitis is a high-prevalence disease, affecting 10 - 20% of the general population. Allergic rhinitis is sustained by an IgE-mediated reaction and by a complex inflammatory network of cells, mediators and cytokines that becomes chronic when exposure to allergen persists. A T(H)2-biased immune response is the background of the allergic inflammation. The current therapeutic strategy is mainly based on drugs (antihistamines, nasal corticosteroids, cromones and decongestants) and allergen immunotherapy. Drugs are (overall) effective in controlling symptoms but do not modify the immune background that leads to allergic inflammation and safety concerns may be present, especially for prolonged treatments. Immunotherapy can modify the allergic response but there is still room for improvement. Nowadays, several approaches are under investigation to optimise the management of allergic rhinitis. On one hand, new drugs and antimediators are being developed. On the other hand, attempts are being made to selectively block relevant signal pathways of allergic reaction. Finally, one of the major goals is to modify the T(H)2-biased immune response by improving the characteristics and modes of action of allergen immunotherapy.     

Angiogenesis: possibilities for therapeutic interventions

Vascular proliferation normally occurd only during embryonic development, the female reproductive cycle and wound healing. Various pathological conditions such as diabetic retinopathy are characterized by persistent, uncontrolled angiogenesis. At the other hand, impaired development of new blood vessels has been found to be related with myocardial infarction. A series of antiangiogenic drugs are currently included in experimental cancer treatment, whereas the failure of ulcers to heal may be limited by increased angiogenesis upon administration of growth factors. In the present review control mechanisms of the vasculature are summarized and therapeutic approaches discussed.     

Perivascular administration of drugs and genes as a means of reducing vein graft failure

Coronary artery bypass surgery is a highly effective and durable therapy of coronary artery disease. Together with internal mammary arteries the saphenous vein grafts are the most important conduits for coronary surgery. We reviewed the topic of local pharmacologic and gene therapeutic treatment approaches to prevent neointimal hyperplasia in vein grafts. Perivascular therapy of veins before arterialization would be a simple approach that avoids systemic side effects of medications. The current data available show that there are promising experimental approaches (in vitro models, animal in vivo models) for pharmacological and gene therapeutic treatment of vein graft failure.     

Animal models for percutaneous absorption

Animal models are important tools to predict human in vivo percutaneous absorption/penetration. Monkey, pig, rat, rabbit, guinea pig, hairless rodents, such as hairless rat, hairless mouse, hairless guinea pig and hairless dog, are among the most used animals for this purpose. Each animal model has its own advantages and weakness or limitation. To better correlate animal data with human skin absorption, we need to be familiar with each animal model's characteristics as well as experimental method and condition. We reviewed the original papers published after 1993 that described permeability of both animal skin and human skin. It showed that monkey, pig and hairless guinea pig are more predictive of human skin absorption/penetration and common laboratory animals, such as rat, rabbit, guinea pig, generally overestimate human skin absorption/penetration. Copyright © 2014 John Wiley & Sons, Ltd.     

Animal models for antiviral chemotherapy

Traditionally animal models have formed a vital part of the preclinical evaluation of new forms of antiviral therapy. A variety of models used in the past or potentially useful in the future are considered in this short review. Several valuable and complex questions concerning virus-drug interactions in vivo have been successfully addressed by means of animal models. Better understanding of drug modes of action and virus pathogenesis in the models enable even more accurate predictions to be made for the outcome of antiviral therapy in man. The complexity of virus infections in man is such that animals are likely to remain an important part in drug evaluation for many years. To this end, new developments such as improved techniques in the production of transgenic animals are opening up a variety of completely novel methods for studying inhibitors of a wider group of viruses in vivo including the human immunodeficiency virus. However, the correct interpretation of animal data requires the critical evaluation of animal models. This review will identify several important difficulties which confront those working on antiviral chemotherapy in animals and which must continue to be addressed if confidence in animal data is to be maintained.     

Animal and cellular models for hypolipidemic drugs

Background: The development of effective and safe lipid-lowering agents should set out from and rely on robust preclinical investigation. Objective: To accomplish this aim, the selection of proper cellular and animal models is crucial. Results: Because lipid-lowering agents are ultimately supposed to reduce the atherosclerotic burden in the arterial wall, they need to tackle directly or indirectly the multifactorial nature of atherosclerotic disease. Hence, these drugs may essentially prevent triglyceride-rich lipoprotein assembly or enhance low-density lipoprotein (LDL) clearance through the LDL or related receptors in the liver. Established animal models such as the apolipoprotein E- and the LDL-receptor knockout mice are widely used to test drug actions on these pathways. A different approach is testing the ability of candidate drugs to increase plasma high-density lipoprotein (HDL) levels. More recently, the focus has shifted to drugs enhancing HDL function rather than just plasma HDL levels. This in turn requires in vitro and particularly in vivo models of reverse cholesterol transport, which have become available by now. Conclusion: A positive outcome of preclinical studies is necessary but not sufficient for an investigational new drug to be eventually approved for clinical use.     

Transgenic mouse models of Alzheimer disease: developing a better model as a tool for therapeutic interventions

Alzheimer disease (AD) is the leading cause of dementia among elderly. Currently, no effective treatment is available for AD. Analysis of transgenic mouse models of AD has facilitated our understanding of disease mechanisms and provided valuable tools for evaluating potential therapeutic strategies. In this review, we will discuss the strengths and weaknesses of current mouse models of AD and the contribution towards understanding the pathological mechanisms and developing effective therapies.     

Animal models of pulmonary infection in the compromised host: potential usefulness for studying health effects of inhaled particles

Pulmonary infection leading to pneumonia is a significant cause of morbidity and mortality worldwide. Airborne particles have been associated with pneumonia through epidemiological research, but the mechanisms by which particles affect the incidence of pneumonia are not well established. The purpose of this review is to examine the potential of animal models to improve our understanding of the mechanisms by which inhaled particles might affect the incidence and resolution of pulmonary infection. The pathogenesis of pneumonia in most animal models differs from that in humans because humans frequently have underlying diseases that predispose them to infection with relatively low doses of pathogens. Normal, healthy animals lack the underlying pathology often found in humans and clear bacteria and viruses rapidly from their lungs. To overcome this, animals are administered large inocula of pathogens, are treated with agents that cause mucosal lesions, or are treated with immunosuppressive drugs. Alternatively, pathogenic bacteria are protected from phagocytosis by encasing them in agar. No one animal model will replicate a human disease in its entirety, and the choice of model depends upon how well the animal infection mimics the particular human response being examined. The advantages and disadvantages of animal models in current use for bacterial and viral infections important in the etiology of human pneumonia are reviewed in detail. Considerable data indicate that prior exposure to particles compromises the ability of experimental animals to resolve a subsequent infection. In addition, information is available on the effects of particle exposure on various portions of respiratory defense including phagocytic function, ciliary movement, inflammation, and antibody response in the absence of infection. In contrast, little research to date has examined the consequences of particle exposure on the host defense mechanisms of animals already infected or on their ability to resolve their infection.