Chapter 025, Guinea Pigs as Experimental Models (American College of Laboratory Animal Medicine)

These findings could provide specific targets for gene or drug therapy [ 76 ]. Finally, the pain phenotype describes the development of OA pain due to inflammation and abnormal bone remodeling in the joint [ 43 , 77 ]. The development of anti-inflammatory and pain medications would benefit patients in this phenotype. Although other clinical phenotypes have been described [ 78 — 82 ], this proposal serves as the closest classification to understand the pathogenesis of the disease and its correlation to the animal models. These five phenotypes may also prompt increased discussion of the disease as we make new discoveries on its pathophysiology.

Osteoarthritis models have classically been categorized into spontaneous and induced models. For simplicity, the models have been grouped here into two basic classes of OA Fig. The post-traumatic phenotype can be studied by post-traumatic OA models. The metabolic phenotype can be studied by surgical and naturally occurring animal models tailored to study the effect of obesity and other metabolic causes of OA such as diabetes and estrogen imbalance [ 83 — 88 ].

The genetic phenotype has been explored using rat models of anterior cranial cruciate ligament ACL transection and medial meniscectomy using gene expression analysis [ 89 ]. In addition, other studies using small and large animal models exist in the literature to find targets for drug or gene therapy [ 76 , 90 , 91 ]. Lastly, pain phenotypes can be studied using pain models of OA. They show considerable overlap with PTOA models. We will discuss these models in the following sections.

Spontaneous models are the hallmark of primary osteoarthritis Fig. The occurrence of slowly progressing OA in certain animals mouse, guinea pig, dog, rabbit, and horse closely simulates the natural progression of human primary osteoarthritis and are commonly used as naturally occurring OA models [ 12 , 13 , 16 ]. In addition to this, various transgenic mouse models genetically modified models have been designed which have the ability to develop OA without intervention.

Spontaneous models rely on these pathological changes rather than post-traumatic alterations. Animals used in spontaneous models can also be used to study induced surgical osteoarthritic changes. Moreover, these animal models serve as a platform to compare spontaneous and induced osteoarthritis.

Since these animals develop OA much more rapidly and extensively than other surgically induced models, spontaneous OA can be observed to develop in one joint and induced osteoarthritis created in the contralateral joint in these animals for direct comparison [ 21 , 92 , 93 ]. A major drawback of spontaneous models is the time required for the injury to develop. Each animal has to be followed to maturity before OA develops.

This lengthy experimental time makes it difficult to conduct short-term studies. Yet, this ensures that the results closely mimic the slow progressive changes noted in human POA [ 12 ]. Another disadvantage is the cost of this study. The cost of housing increases as these animals have to be followed over a prolonged period of time.

Mice, rabbits, guinea pigs dogs, sheep, and horses exhibit naturally occurring OA. The Dunkin Hartley guinea pig has been the most widely used animal to study naturally occurring OA [ 12 , 93 , 96 ]. These animal models give the best representation of POA in humans. One advantage they have over larger animal models is their rapidity of growth to maturity [ 95 ].

Background

Another advantage is that they develop lesions markedly similar to human subjects, furthering the possibility of their use in therapeutic and pathogenic studies [ 93 ]. The guinea pig is also a great natural model to study inflammation in the joint [ 97 ]. Rabbits have also served as good models to study the disease. This species may help aid the development of bioengineered treatment of cartilage defects [ , ]. Dogs have been beneficial as natural models in preclinical trials of therapeutic intervention [ — ]. The horse articular cartilage is the most comparable to humans.

They have been used to study articular cartilage repair and osteochondral defects [ 16 , , ]. This animal provides a naturally occurring model to study bone remodeling, which leads to bone cysts and osteophyte formation [ , ]. This could aid the development of treatment to combat these changes in humans, especially in POA.

The sheep model has been successful in studying early cartilage changes in OA [ ]. Due to their anatomical similarity to humans, this model can be used to study meniscus changes and related treatment techniques [ — ]. The major advantage of mouse models in OA studies is the ability to genetically modify them or breed specific strains particularly susceptible to OA.

Therefore, transgenic mice have been used extensively as genetically modified species to study OA. The gene mutations in these animals are designed to either protect the animal from OA or worsen a structural change in the disease [ 21 ]. Consequently, these studies have helped to establish the molecular basis of OA including the effect of pro-inflammatory cytokines on OA development [ 21 , ]. For example, knockout mice lacking a particular protease could be resistant to developing OA [ ].

Genetically modified models have played a crucial role in understanding specific genetic contributions to the pathogenesis of OA [ 18 , ]. However, therapeutic interventions targeting these specific genes do not take into account other contributing genes that participate in the pathogenesis of the disease [ 16 ]. This may reduce the translatability of results to clinical trials.

As mentioned earlier, secondary OA is a condition occurring in the presence of specific causes or risk factors. Although these causes include congenital, calcium deposition, bone, joint e. This is especially true in animal models [ 21 ]. Due to its advantages, the last few years have seen significant interest in developing a number of non-invasive models in mice, dogs, and rabbits. These could serve as viable alternatives to induced models of OA.

The next few sections discuss the differences between the invasive and non-invasive models to study PTOA. Induced invasive models have been used to study the effect of drugs on the disease process. They can further be classified into surgically induced and chemically induced models.

The rapid induction of osteoarthritis by these models ensures that the study can be performed in a shorter time frame. Yet, a weakness of induced models is that they have no correlation to natural degenerative changes in human degenerative osteoarthritis [ 12 ]. However, surgically induced models have been used to study the pathogenesis of post-traumatic osteoarthritis, an example being subchondral bone changes [ ].

A large number of surgically induced OA models exist in the literature. Commonly used models include anterior cruciate ligament transection ACLT; most common , meniscectomy partial and total , medial meniscal tear, and ovariectomy. Surgical models involve the use of aseptic techniques to surgically induce OA in animals.

The results are highly reproducible and progress rapidly. This makes surgical models an excellent choice for short-term studies. Yet, this invasive rapid induction may be too quick in order to follow the early stages in OA development as well as for measuring early drug treatment.

The ACLT model was the earliest well-known model and is the most commonly used surgical model in OA research today [ 12 , 16 ]. The model imitates the degradation of articular cartilage after ACL rupture. Compared to meniscectomy, the OA lesions in ACLT develop more slowly, increasing the ease of use of this model in pharmaceutical studies [ ]. The anterior drawer test is used to test the success of this procedure [ 12 ].

The stifle in these animals is large enough for easy replication of the procedure. The goat in particular has the closest anatomy to the human knee [ ]. In animals, as in humans, meniscectomies lead to osteoarthritic changes in the joint [ , ]. A partial meniscectomy causes a destabilization of the joint leading to rapid degeneration and a more severe case of osteoarthritis than ACL transection [ ]. The site for the surgical procedure, medial or lateral, varies by animal model.

This is due to the differences in load bearing of each animal on its menisci. For example, humans, as with guinea pigs, usually load the medial side of the knee. This may vary based on the varus or valgus alignment of the knee leading to medial or lateral osteoarthritis, respectively [ 41 ]. In contrast, rabbits load their lateral meniscus more than their medial [ 13 ]. This is why rabbits develop more severe lateral osteoarthritis when surgery is performed on that meniscus. Just as partial meniscectomies, total meniscectomies follow a similar mechanism of injury.

Nevertheless, this model leads to much more severe osteoarthritic changes in animals. Dogs are the most widely used animals for this procedure mainly due to the volume of literature on their application. Alternatively, medial meniscal tear in humans causes joint instability and cartilage degradation. The medial meniscal tear model in animals is achieved through transection of the medial collateral ligament in the knee [ 13 , 16 ].

It causes proteoglycan and chondrocyte loss leading to cartilage degradation. Rats and guinea pigs are the most studied examples of animals using this model. The advantage of guinea pigs in the study is the ability to compare the contralateral joint for natural osteoarthritic changes [ 13 ]. Finally, ovariectomy works on the human principle that post-menopausal individuals develop osteoporosis, consequently leading to OA. Thus, estrogen serves a protective function to the development of OA [ ]. New Zealand rabbits have been recommended to study the direct effect of estrogen deficiency to the development of OA [ 87 , 88 , ].

Other animals include mice, rats, guinea pigs, and sheep [ — ]. Although this model can be used to study therapeutic intervention [ ], it is believed that this model would be more useful in determining other pathological pathways to the development of OA due to its unknown pathophysiology [ 12 ]. Chemically induced models mostly involve the injection of a toxic or inflammatory compound directly into the knee joint. This model can be used to study the effects of drugs on the inflammation or pain caused by these substances. Papain, sodium monoiodoacetate, quinolone, and collagenase are some of the chemicals employed to induce OA in animals.

They eliminate the need for surgery and avoid possible infection issues in some animals. Their ease of induction and reproducibility are advantageous in designing short-term studies. Although less invasive than surgical models, chemical models have a unique pathophysiology which has no correlation to that of post-traumatic OA. This explains why they are mainly used to study the mechanism of pain and its use as a target for drug therapy [ 12 ]. Papain is a proteolytic enzyme which was historically used in OA induction.

It breaks down proteoglycans, important components of cartilage that give it compressive resistance through the absorption of water [ 33 ]. However, the use of papain for an OA model is becoming increasingly rare. It inhibits glyceraldehydephosphate dehydrogenase of the Krebs cycle leading to the death of chondrocytes.

This in turn causes osteophyte formation and articular cartilage degradation [ ]. MIA-induced OA model is regularly used to measure pain behavior and drug therapy to resolve the pain in animals. This model may be more predictive of drug efficacy than other pain models used to test OA drugs [ ].

It is generally used in mice and rats [ ]. Other toxic compounds such as quinolones and collagenase have been used. Oral quinolone antibiotics usually cause growth defects in young children. This occurs through their action on the epiphyseal growth plate of their bones. It can also cause loss of proteoglycans and chondrocytes through systemic administration [ 12 , ]. This mechanism serves the use of this antibiotic in causing lesions in animals, though it does not cause osteophyte formation [ ].

As mentioned previously, the release of collagenase in OA leads to the degradation of proteins in the articular cartilage. As a chemically induced model, intra-articular administration of collagenase breaks down type I collagen within the cartilage leading to decreased collagen matrix in the tendons and ligaments, consequently leading to joint instability [ , ].

This makes it an excellent model to study pain behavior corresponding to osteoarthritic changes [ ]. Inflammatory changes caused by infection would affect the results of the experiment. Some of these shortcomings can be resolved with non-invasive models. These models produce an external insult to the joint of study, negating the need of any chemical or surgical intervention. They are powered by machines which cause injury through mechanical impact, without causing a break in the skin of the animal.

This injury causes osteoarthritic changes similar to induced animal models in the animal being studied. A notable advantage is that the injury can be created with precision, which is not always feasible in the more invasive models [ 4 ]. Given that PTOA usually occurs after external joint trauma to young human adults, the biomechanics of the human injury that lead to PTOA can be replicated. The theory behind the invention of non-invasive mouse models is that confounding factors, which may affect the results of induced OA models, can be eliminated while reproducing human traumatic injuries in animals [ 4 , ].

Moreover, the early phases of OA can be studied using these models. Thus, the knowledge generated by these models could become essential in developing early therapeutic intervention for PTOA [ ]. With proteoglycans such as aggrecan being a major component in cartilage, continuous loss of Safranin-O staining is indicative of proteoglycan loss, thus loss of cartilage. Three major mouse models for non-invasive OA have been described Fig. In this model, the flexed knee of the anesthetized mouse is fixed on a triangular cradle while an indenter provides the force of impact.

The indenter causes a closed fracture of the joint, and the severity of changes can be varied by adjusting the amount of force applied. These fractures could replicate acute trauma in the human condition from high energy impacts such as a front end motor vehicle accident [ 4 ]. Intra-articular fractures are a known cause of PTOA, and there is a need for studies to better aid the prevention, treatment, and understanding of the disease [ — ].

Experimental animal models for COPD: a methodological review

Therefore, this serves as an ideal model to study the pathogenic changes that occur in joint degeneration after acute injury. This causes a closed fracture of the tibial plateau. This model can also cause an ACL rupture at higher loads. The direction of the load between the upper and lower loading cups is shown.

Location of strain gauges ion the apparatus a , lateral and b , medial on the tibial mid-shaft are also shown. Taken with permission from Furman et al. In this model, an axial load is applied to the stifle leading to an anterior displacement of the tibia relative to the femur See Fig. The load could be applied in cycles over a period of time or as a one-time single overload if the goal is to cause an ACL rupture. The long-term effects of injury can be studied, by applying several cycles over a period of time and by adjusting the load on the joint to be studied.

With repetitive compressions over a period of time, this model could be used to study subchondral bone changes. However, the contralateral limb cannot be used as a control with a longer loading period of the ipsilateral limb [ ]. Thus, cyclic articular cartilage tibial compression CACTC is the preferred model to study the effect of chronic overuse injury on the development of OA. This tibial compression overload leads to a mid-substance rupture of the ACL. ACL ruptures due to cyclic tibial compression produce comparable injury pathology to human ACL rupture.

The injury pathology generated is also analogous to the animal ACL transection model but without the need of invasive surgery. If the load and speed are strong enough, the result is either a mid-substance rupture of the ACL or, at lower loads or speeds, an avulsion fracture of the ACL from the underlying bone [ ]. This model is ideally suited to study early osteoarthritic changes and the effect of early treatment following acute low energy impacts, such as a sports injury to the knee [ , ].

However, long-term studies cannot be accomplished due to bone osteophytic changes which serve to stabilize the joint [ ]. The application of cyclic tibial compression in rats has recently been examined [ ]. This experiment, the first of its kind, included the use of motion capture and quantitative joint laxity testing. Laxity of the lateral collateral ligament LCL also occurred in this experiment. It expedites the successful application of non-invasive models in rats. Similary, this could encourage the use of the tibial compression model in larger animals.

One advantage of a larger animal model over the corresponding mouse model is the possible use of in vivo magnetic resonance imaging MRI to observe osteoarthritic changes throughout the study [ 16 ]. Another advantage is that it may generate a closer approximation of drug efficacy in PTOA studies. However, the effects of genetics on the development of PTOA can be readily studied in genetically modified rodents and not in larger animals [ ].

In the last two decades, various non-invasive canine models have been developed to investigate various aspects of OA [ — ]. Potential therapeutic options are currently under development using these models. Although several breeds such as the Labrador, golden retriever, and German shepherd have been used in canine models, the beagle dog is the commonly used animal in non-invasive models. Transarticular impact involves the use of a dropping tower to cause an impact on the patellofemoral joint of the immobile knee See Fig.

Subsequently, canine models have been used to test the early changes of osteoarthritis that occur in articular cartilage due to joint impact trauma [ 12 , ]. They were specifically designed to study these changes and could be used to produce osteochondral lesions with higher loads [ , ]. In one study, this model illustrated that the high impact on these joints without fracture will lead to healing within a year of injury [ ].

This is despite early MRI images showing adverse changes following the impact. Biopsies served as the histological specimens in these studies, negating the need for euthanasia to harvest tissue samples. This model has the capability to aid research on cartilage healing or surgical joint replacement in future studies of osteoarthritis. The use of MRI to study outcomes [ , ] points to a non-invasive measure of disease outcome by replacing the need for histopathology. Additionally, immunofluorescence on unfixed cryosections has been used in this model to study the degenerative changes of OA [ ].

The right lower limb is held rigidly with the animal lying in lateral recumbency. Adapted with permission from Lahm et al. Note the dropping tower used to apply the load on the patellofemoral joint. Analogous to canine models, a subset of lapine models involve transarticular mechanical impact on the patellofemoral joint Fig. A sub-fracture impact is directed toward the rabbit knee leading to osteoarthritic changes [ — ].

Some of the rabbit models also included an exercise program to induce changes in bone remodeling [ ]. In addition, some femoral condyle impact models that utilize a pendulum swing to replicate knee trauma have been described [ — ]. Impact experiments were performed by dropping a mass with a padded impact interface A 3. Taken with permission from Ewers et al.

The results of non-invasive animal models are highly reproducible. What may give them a greater advantage over induced models is the precision of the results on each animal. They also closely simulate human injuries leading to PTOA. But even with the possible benefits of using non-invasive models, there are still limitations to its use.

Recent literature have noted the effect of age, sex hormonal status , and mouse strain on the results of this model as possible limitations [ , ]. However, recording the results using the Animal Research: These are a set of strategies designed to give information on how to record the conditions of the experiment and report the results. Another possible limitation is the need for properly trained personnel to use these custom modified equipment [ 4 ].

These modifications are not universally available, further limiting the use of non-invasive model. Even with its precision, proper placement of the joints in the equipment is required to reduce variation in the results. Furthermore, the angle of knee flexion may affect the results of the experiment. These factors may account for the differing results already seen between similar studies. For example, in one study by Radin et al. Chronic pain and discomfort are the hallmarks of OA. Thus, the evaluation of chronic pain along with the molecular pathways leading to OA is an integral part of understanding the pathogenesis of OA and developing successful treatment regimen for the disease.

However, unlike the possible molecular pathways leading to OA, evaluation of chronic pain is highly complex due to the inherent variability associated with the experiments and interpretation of the results [ ]. Animal models pertinent to understanding the basic pathogenesis and disease progression of OA have been established, courtesy of standards such as the Osteoarthritis Research Society International OARSI initiatives for uniformity across the studies.

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However, till date, no such standards exist for the study of chronic pain [ ]. In addition, animals behave differently when under pain, depending on the nature of the species. For instance, rats, mice, and guinea pigs, which are prey animals, tend to hide their pain as a natural instinct as this would attract predators. However, the same behavior cannot be said to be true for higher order animals such as dogs and cats [ 18 ]. For instance, when dogs are under distress they tend to express their pain by not being active, whining, and licking.

Cats on the other hand hiss and hide the injured or painful site. Thus, movement changes due to OA in dogs and cats can be better studied than smaller animals [ ]. Despite their marked differences in behavior when under pain, small animals are widely used to study OA-related pain. The potential reasons why higher order animals are not preferred, at least in preliminary investigations, are due to their prohibitive cost, housing, maintenance, and in some cases, ethical concerns. On the contrary, higher order animals are expected to replicate at least some features, since they are more similar anatomically and biomechanically [ ].

Various subjective models based on mechanical, thermal, anatomical, and chemical changes have been reported for both smaller as well as larger animal models. OA induced in animals via surgical, chemical, and mechanical means are commonly used to evaluate OA related pain [ ].

Induction methods frequently employed by chemical means include MIA, carrageenan, and papain, while, surgically, employed means include anterior cruciate ligament transection, medial meniscal transection, and meniscectomy. Of these, MIA is the most widely reported method ca. The extent of pain in small animals with OA is commonly assessed by techniques such as the rotarod test, incapacitance test, gait analysis, spontaneous behavior, mechanical and thermal sensitivity, paw withdrawal, and knee extension.

For larger animal models, test methods such as gait analysis and lameness by proxy are most frequently utilized. Various pain scales are used in humans and based on the descriptive nature of pain. Unlike humans, VAS-based scoring system may not be feasible with all animal models. But it would be feasible to use these scales with domesticated animals such as dogs and cats, whose owners would be able to understand the cues exhibited by the animals.

Therefore, the owner could stand as a proxy for the animal [ ]. In addition, imaging techniques such as MRI has been shown to correlate exceptionally well for osteoarthritic pain in humans [ , ]. Although spontaneous models have been used to study obesity in relation to increased joint loading and osteoarthritis development, there are specific joint loading models used to measure the impact of activity and knee malalignment on OA development.

Race horses have served as equine models for the study of microstructural changes in articular cartilage due to overloading of the joint. These changes have occurred despite a grossly intact hyaline cartilage [ , ]. Lapine models have been shown to exhibit degenerative changes in the side of increased chronic loading in the knee joint, with the use of a mechanical varus-loading device [ ]. A similar experiment was performed in rats to study gait changes after medial knee compartment overload [ ]. As mentioned earlier, the two major goals of OA research in animals are to either study the pathology of the disease or test the efficacy of treatment.

Techniques such as histopathology, biomarker measurements, imaging, pain measurement, and biomechanical assessment have proven useful to achieve these goals. Typically, microscopic studies e. But recent advances in techniques, for instance micro-MRI, have enabled visualization of critical sections such as bone marrow lesions in smaller animals [ ]. Their applications in humans and subsequent use in animal models have served to improve our understanding of the disease.

Though no one particular standard offers exceptional correlation to OA, histopathology is currently the gold standard for assessing of OA in animal models [ ]. The histology samples, in conjunction with immunohistochemical staining, can be used to classify and measure the degree of degeneration in the joint. One of the first techniques that were used to grade OA was reported by Collins et al. Collins and co-workers [ — ] in a series of articles reported the variations in the uptake of 35 S and subsequent chondroitin-sulfate synthesis by cartilage cells in the costal and articular cartilages of the patella in humans with different stages of OA.

Their observation on articular cartilage tissues obtained from human cadaver was that sulfate utilization was higher and commensurate with the degree of damage to articular cartilage [ ]. They further showed that contrary to the popular belief, damage to the articular cartilage is not caused by loss of chondrocytes [ , ]. In fact, increased activity of sulfate utilization by chondrocytes in damaged cartilage pointed to active chondrocytes in those tissues. To further enhance the applicability of this technique, Collins et al.

Collins and co-workers [ ], in addition, developed a scoring system based on histological data to classify the knee based on the level of damage to the cartilage. The extent of damage in the knee was classified into four groups: The first group, i. The third group, grade II, illustrated fibrillations extending into the deep zones, and in the last group III and IV , significant loss of cartilage along with deep exposure of the bare bones. A major drawback of this system was the specimens were obtained from either surgical removal of the patella or from necropsies.

Hence, neither the pathogenesis of the disease nor the progression of OA can be studied by this model. A point-based grading system was subsequently developed by Mankin et al. Here, surgically removed human femoral heads were histopathologically correlated with biochemical changes in DNA and carbohydrate synthesis.

Higher carbohydrate content correlated with lower disease progression, even though the same could not be concluded for DNA. From the experimental observation, a new point grading system based on cellular, histochemical, and biomechanical changes was created [ ]. Although the Mankin score and previous grading systems were extensively used in animal models to study OA, they present challenges while investigating early or intermittent stages of OA.

Several modified grading systems such as modified-Mankin or modified-HHGS have therefore been developed to address the poor reproducibility and intra and inter-observer variations of Mankin scoring system [ ]. At the same time, Mankin scale can be successfully used to study sodium monoiodoacetate induced OA due to the rapid progression of the disease to form terminal OA. To enhance reproducibility, decrease intra- and inter-observer variations, and standardize the assessment and reporting techniques across animal models, the OARSI formed a working group in to develop a standard OA grading system [ 54 ].

The five cardinal principles the working committee used to determine ideal OA histopathological system were simplicity, utility, scalability, extendibility, and comparability [ ]. Some of the remarkable progress made by this committee were established clinical trial end points, defined subsets of OA and guidelines to evaluate new features of OA apart from cartilage and evaluate histopathology in animal models.

Based on the severity of OA, the working group classified OA into seven grades with grade 0 being uninvolved or intact cartilage and grade 6 involving deformation of articular contour. Unlike the older scoring techniques, the OARSI technique specifically relied on the depth of progression into the cartilage to grade OA. By borrowing concepts from cancer pathology, efforts were also made to designate the severity of OA lesions by stages [ 16 ].

The OARSI working group provides this information through a released set of guidelines for each animal used in animal models [ 51 , 54 , — ]. Traditionally, OA is evaluated with radiographs in the clinic to demonstrate joint space width JSW and the formation of osteophytes [ ]. Radiographs also permit the visualization of subchondral sclerosis and subchondral cysts [ ].

Various animal models with rats [ ], rabbits [ ], and dogs [ ] have been studied using radiography including the most famous Pond-Nuki model dogs [ ]. In rats and rabbits, radiography has been used to study subchondral bone remodeling and joint space narrowing. Recent research, however, suggests cartilage loss alone is not the sole contributor to OA, but changes in the morphology of menisci also play an equally responsible role [ — ].

Unfortunately, radiography, which is the current gold standard for imaging OA, lacks sensitivity to visualize such variations [ ]. Moreover, changes in the flexed position used in the follow-up imaging also might lead to conflicting conclusions, which severely restricts the application of radiography in OA [ ]. In addition, radiography allows only late stage visualization of OA and does not allow direct visualization of cartilage itself.

To some degree, utilizing computer tomography CT arthroscopy circumvents this problem. Unfortunately, this technique is invasive [ ]. Despite these disadvantages, radiography is still widely used in the clinical setting. Magnetic resonance imaging MRI , unlike radiography, is capable of visualizing not only the cartilage but also the menisci, ligaments, synovium, and biochemical markers pertaining to OA [ ].

By virtue of its ability to phase contrast tissues, it can distinguish and study individual tissues. Despite its high cost, due to its potential and capabilities, MRI is a fast advancing tool replacing radiography in characterizing and detecting early stages of OA [ 33 , , ]. For high resolution imaging, a minimum of 1 Tesla T scanners are typically required. Currently, the most widely used models in clinics are the 1. But recently, the 3-T model has been introduced and is fast becoming the choice for imaging [ ]. With significant advancements in instruments and hardware and with its superior capability, MRI, unlike radiography, is expected to take a leading role in future animal model experiments to study various aspects of OA [ ].

The difficulty in utilizing radiology has prompted the development of these alternate techniques to study OA in animals. Till date, MRI has been utilized to study various animal models, small and large, including rat, rabbit, guinea pig, dog, and non-human primates rhesus macaque [ — ]. For example, in rat osteoarthritis models, several osteoarthritic changes can be monitored in vivo with the use of MRI [ — ].

In rabbit models, cartilage thinning and swelling, decrease in proteoglycan content, and mild subchondral changes can be observed which are typically difficult to visualize using radiography [ ]. MRI has also been used to acquire 3D images of cartilage volume loss in a naturally occurring OA caused by obesity in the guinea pig model [ ]. Cartilage is essentially composed of collagen, proteoglycans, and water [ 26 ]. All three components play a complex role in the functioning of the tissue. Any change in their composition causes debilitating effect on the tissue and ultimately leads to OA.

That is another reason why radiography ultimately fails in its ability to study OA. Site-specific studies can be fortunately performed, unlike in radiography, by MRI using various techniques such as gradient recalled echo GRE , spin echo SE , fast SE, and 3D SE, which have profound impact in studying the morphological changes of the cartilage during OA [ ]. For instance, T1 in the rotating frame T1-rho works by measuring the spin-lattice relaxation in the rotating frame, and any loss of aggrecan can be measured indirectly by observing the motion of water molecules [ ].

On the other hand, in T2 mapping, an increase in relaxation times indicates the inefficiency of water molecules to exchange the energy inside the matrix [ ]. Typically, the most imaging modalities for OA involve characterizing proteoglycans, but some techniques such as DWI and DTI work by studying the orientation as well as the flow of water molecules through the cartilage.

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In DWI when diffusion sensitizing agents are applied, water molecules possess a random directionality with a uniform signal intensity. However, when it encounters a diffusion, it undergoes a signal drop, which indicates unhealthy cartilage [ ]. DTI, which is an advanced imaging technique, is capable of measuring not only diffusion of water but also the direction of the flow which aids in mapping the cartilage tissue [ ]. MRI, similar to nuclear magnetic resonance NMR spectroscopy, works based on the fact that any atom with odd number of protons with non-zero spin would exhibit magnetic resonance phenomenon [ ].

In that aspect, 23 Na can also be used instead of conventionally used 1 H to image cartilage and other relevant tissues. Despite its high potential to study the cartilage, using 23 Na requires specialized coils which inhibit their clinical use. Their far lower Larmor frequency and concentration at resonance frequency signal strength compared with 1 H further dampens its case to be used for MRI imaging [ ].

But with significant improvements in instrument hardware, it can be envisaged that 23 Na would be a tool of interest in the near future to detect early stages of cartilage changes with OA. Apart from the loss of proteoglycans as described by Collins et al. Plain radiography is incapable of imaging synovial fluid and is thus not used for this purpose. Ultrasound and MRI are the most commonly used modalities to image synovitis. In addition, 2D spin echo and 3D gradient echo are the other two techniques employed to study synovitis. Aside from synovitis, these techniques can detect intraosseous cysts; lesions in the meniscus, bone, and ACL; and subchondral bone defects and can also map articular synovial space.

Ultrasound has found some success in animals and humans to detect other early osteoarthritic changes [ 33 , ]. An added advantage in using MRI is its simplicity in developing a grading system which facilitates uniformity, comparability, and reproducibility across various models.

It is widely used to study bone formation, healing, and remodeling. However, as with radiography, CT even with multisource spiral CT scanners is yet to find any significant application in visualizing OA knee , especially in its initial stages [ ]. However, as mentioned before, it could be an excellent tool to visualize changes in the bone joints, and MRI with its significant advantages can easily replace CT for knee OA. A more invasive version of CT, optical coherence tomography, is frequently used to study the diseased state of cartilage by affixing with an arthroscope.

Also, by combining with other techniques such as MRI and positron emission tomography, CT is expected to make significant contribution in studying early stages of OA [ ]. In addition, by utilizing contrast agents, contrast resolution of the cartilage images can be enhanced. Positron emission tomography PET is a unique technique used primarily in oncology, cardiology, and neuroscience [ ]. It allows measurement of functioning of tissues by using compounds that are short-lived positron emitting nuclides [ ].

Typically, it is used to detect glucose uptake by cells, and fortunately, it can also be utilized for OA as glucose uptake take place in cartilage by proteoglycans. Apart from OA, PET has potential to investigate chondrosarcomas and tumors in the bone [ , ]. In addition to the currently used imagining studies, FRI has shown success in non-invasive mouse models to quantify the biological responses and time course in OA [ ].

In a recent study, bioluminescence has also shown promise in mouse models of osteoarthritis to measure cartilage changes [ ]. For this study, chondrocyte mutation in the CreER T2 protein, which is activated by tamoxifen injection, was successfully applied to mice undergoing joint destabilization studies and treadmill exercises. The technique might well prove useful as a non-invasive imaging modality for future studies of cartilage degeneration.

Biomarkers of cell degeneration and inflammation can serve as a measure of disease progress or treatment outcomes in clinical osteoarthritis. These molecules are precursors or products of metabolism released in the serum, urine, and synovial fluid, and their levels correlate with osteoarthritic changes in the joint. Several biomarkers are commercially available for use in clinical trials [ 6 , 33 , , ].

Associated Data

Other clinical biomarkers include serum hyaluronic acid HA , serum and urine Coll a peptide of the alpha-helical region of type II collagen and its nitrated form Coll NO 2 , and YKL also known as chitinase 3-like 1, CHI3L1, or cartilage glycoprotein [ — ]. Despite their availability, further investigation into the applicability of these markers in clinical research is needed due to the lack of consistency in results of its application [ ]. Research is ongoing to evaluate new biomarkers for preclinical and clinical studies.

In animal models of osteoarthritis, this research also assesses the usefulness of biomarkers in studying early osteoarthritic changes and the effect of treatment. This was found to correlate with results in humans using this assay [ ]. Serum xylosyltransferase 1 Xylt1 is increased in mice models of OA under a background of mice with high bone forming potential. This study suggests an application of this marker in studying OA risk in young adults [ ].

There have also been promising results in the application of biomarker research in other small animal models. In rats, this was accomplished using immunohistochemical staining of histological sections [ ].

Experimental animal models for COPD: a methodological review

The MIA model has been utilized in rats to develop an aggrecanse model of cartilage degradation, using aggrecan neoepitope release in synovial fluid to follow these changes [ ]. Rabbit models of ACLT have shown a similar correlation of the biomarkers HA and chondroitin-sulfate epitope, with the severity of OA in the joint [ ]. Guinea pigs have been assessed to determine the usefulness of biomarkers in spontaneous models [ 97 ].

In recent years, several biomarker research studies have involved the use of dog models. Dogs share the same MMPs as humans and biomarker research can be translated better to clinical studies [ ]. Serum levels of fetuin B and complement C3 were also elevated in this surgical model in another study [ ]. Another study by Alam et al. These substances could serve as possible biomarkers to study early OA changes in other animal models and humans.

Tenascin-C is another biomarker found in both canine and human synovial fluid during osteoarthritic changes, and this substance could play an additional role in increasing joint degradation [ ]. Regrettably, no gold standard exists in the literature for animal studies and translation from in vitro to in vivo studies, then clinical studies, has met with difficulties [ ]. In animal studies, biomarkers are most useful when taken directly from the joint synovial fluid [ 16 ]. Yet, this is not always feasible in the smaller joints of small animal models such as mice; aspirated samples from these studies would be insufficient.

Although biomarkers could be measured from other sources, such as urine samples, their levels are influenced by other diseases or metabolic conditions just as in clinical studies. Therefore, more biomarkers have been developed for animals with larger joints such as guinea pigs and dogs [ 97 , ]. Other animals utilizing biomarkers are sheep and horses [ , ].

Used in conjunction with imaging studies, biomarkers can give a greater characterization of the disease process in both large animal models and humans [ 33 , , ]. Each osteoarthritic model, which can also be used in combination with other models, has proven useful in improving our understanding of OA.

The disease has been shown to develop through an inflammatory mechanism. Several small and large animal models have been developed to make these findings, and these models can be related to the disease etiology. Subsequently, the drugs or treatment methods tested in animal models could provide abundant benefits to human subjects with the disease.

Yet, there is a shortage of literature on specific translational effects of these animal models and their relationship to human clinical outcomes of tested drugs. Although it is well known that the efficacy of treatment in preclinical models do not always translate to the human condition, translational data providing this information would help in developing improved animal models. There is also a limited amount of literature on other animals such as mini-pigs or cows [ 16 ]. Although these models could potentially not be as anatomically relevant or well-studied, their abundancy ensures availability for studies.

AMAZING - The Benefits Of Animal Testing

An investigation into the disease process in these animals with non-invasive models has the potential to be relevant to OA studies. Non-invasive animal models are great alternatives for the study of OA in mice, dogs, rabbits, and possibly rats. But there is a dearth of literature on non-invasive models for larger animals. These would be needed as there is a great potential of these models to improve OA studies. They are reliable tools for studying early OA changes that would not be possible in invasive induced models. Several benefits of mimicking the human OA condition have been found. However, it still mimics just PTOA.

This model simulates chronic joint overuse. In contrast, spontaneous models will remain the best possible models to study POA until an alternative can be found. There are also some problems with uniformity in the results across studies. Although the OARSI provides guidelines in animal OA research, as of the writing this paper, there are no guidelines to address non-invasive animal models. The successful use of ultrasound and MRI, as well as the increasing usefulness of PET, in both humans and animals would significantly improve studies of OA.

These imaging studies are emerging as important non-invasive alternatives to histopathology in animal models and would allow for disease observation in vivo. However, there is a need for standardization of these procedures before they can be extensively used to maintain uniformity and ease of comparison across all studies. Despite the innovations in OA research, results of preclinical treatment studies have shown poor translation to clinical trials.

Hence, these treatment techniques would be inappropriate in treating POA. Another problem with animal model experiments lies with data collection in these studies. Certain important factors, such as animal husbandry conditions and the sex of the animal, have been excluded from the results but may show a great effect on the outcomes [ 16 ]. This review presents an overview of animal models currently used to study the pathogenic changes in OA along with the resulting symptoms and the effect of treatment on the disease.

New models are being designed to study more aspects of the disease. Nevertheless, additional exploration would still be needed by the researcher in determining the best model and expected outcomes for their study. These include the cost, housing, type of animal, and length of experiment which should be further investigated to make the best possible choice for their study. ELK wrote the first draft of the manuscript, with GN contributing to drafting.

All authors contributed to revising the manuscript and approved the final draft. National Center for Biotechnology Information , U. J Orthop Surg Res. Published online Feb 2. Kuyinu , Ganesh Narayanan , Lakshmi S. Nair , and Cato T. Author information Article notes Copyright and License information Disclaimer. Received Oct 23; Accepted Jan This article has been cited by other articles in PMC. Abstract Osteoarthritis OA is one of the most commonly occurring forms of arthritis in the world today. Osteoarthritis, Animal models, Non-invasive models, Post-traumatic osteoarthritis, Osteoarthritic phenotypes, Imaging, Outcomes.

Background Osteoarthritis OA is a complex disease process involving the whole synovial joint. Open in a separate window. Osteoarthritis pathogenesis OA was originally believed to be caused by the wear and tear of the articular surfaces in the joint. Table 1 Proposal for differentiation of clinical phenotypes of OA.

Common animal models used for OA For animal models of OA, the stifle knee is the joint regularly used. Classification of osteoarthritis and animal models OA has typically been classified into primary idiopathic and secondary OA [ 68 — 70 ] Fig. Naturally occurring models Mice, rabbits, guinea pigs dogs, sheep, and horses exhibit naturally occurring OA. Genetically modified models The major advantage of mouse models in OA studies is the ability to genetically modify them or breed specific strains particularly susceptible to OA. Secondary OA As mentioned earlier, secondary OA is a condition occurring in the presence of specific causes or risk factors.

Surgically induced models A large number of surgically induced OA models exist in the literature. Chemically induced models Chemically induced models mostly involve the injection of a toxic or inflammatory compound directly into the knee joint. Table 2 List of non-invasive OA models listing their uses, advantages, and disadvantages.

Model Usefulness and advantages Disadvantages IATPF Reproduces PTOA from high energy impact Not useful for chronic injuries Used to study early OA changes after acute injuries or fractures Not useful for low energy impact Severity of lesions can be adjusted CACTC Reproduces chronic joint overuse Not useful for acute injuries Used to study early OA changes after chronic overuse injury Several cycles and weeks needed to cause severe changes Tibial compression overload Reproduces PTOA from low energy impact Not useful for long-term studies Used to study severe early OA changes after acute injuries Cannot use contralateral limb as control in long-term studies One single load needed Transarticular Impact Reproduces PTOA Cannot use contralateral limb as control in long-term studies Severity can be adjusted Potential to study surgical knee replacement Readily available non-invasive studies.

Table 3 Pros and cons of invasive versus non-invasive animal models of OA. Mouse models The theory behind the invention of non-invasive mouse models is that confounding factors, which may affect the results of induced OA models, can be eliminated while reproducing human traumatic injuries in animals [ 4 , ]. Intra-articular tibial plateau fracture The earliest of the non-invasive mouse models is the intra-articular tibial plateau fracture IATPF; see Fig. Canine models In the last two decades, various non-invasive canine models have been developed to investigate various aspects of OA [ — ].

Lapine models Analogous to canine models, a subset of lapine models involve transarticular mechanical impact on the patellofemoral joint Fig. Pain models Chronic pain and discomfort are the hallmarks of OA. Table 4 Commonly used animal models and outcome measures for pain in osteoarthritis. Miscellaneous models Although spontaneous models have been used to study obesity in relation to increased joint loading and osteoarthritis development, there are specific joint loading models used to measure the impact of activity and knee malalignment on OA development.

Measures of disease outcome As mentioned earlier, the two major goals of OA research in animals are to either study the pathology of the disease or test the efficacy of treatment. Histopathology Though no one particular standard offers exceptional correlation to OA, histopathology is currently the gold standard for assessing of OA in animal models [ ]. Biomarkers Biomarkers of cell degeneration and inflammation can serve as a measure of disease progress or treatment outcomes in clinical osteoarthritis.

Concluding remarks Each osteoarthritic model, which can also be used in combination with other models, has proven useful in improving our understanding of OA. Conclusions This review presents an overview of animal models currently used to study the pathogenic changes in OA along with the resulting symptoms and the effect of treatment on the disease. Footnotes Competing interests The authors declare that they have no competing interests. Contributor Information Emmanuel L.

The epidemiology and impact of pain in osteoarthritis. Neogi T, Zhang Y. Rheum Dis Clin N Am. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Non-invasive mouse models of post-traumatic osteoarthritis. Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. OARSI guidelines for the non-surgical management of knee osteoarthritis. Cochrane Database Syst Rev. Glucosamine and chondroitin for knee osteoarthritis: Osteoarthritis—a case for personalized health care? Useful animal models for the research of osteoarthritis.

Eur J Orthop Surg Traumatol. Animal models of osteoarthritis. J Musculoskelet Neuronal Interact. Wendler A, Wehling M. The translatability of animal models for clinical development: On the predictive utility of animal models of osteoarthritis. Animal models of osteoarthritis: Experimental models of osteoarthritis: Little CB, Zaki S. Rheumatology Oxford ; 51 Man GS, Mologhianu G. Osteoarthritis pathogenesis—a complex process that involves the entire joint. Pathogenesis of post-traumatic OA with a view to intervention. Best Pract Res Clin Rheumatol.

Characterisation of human knee meniscus cell phenotype. The basic science of human knee menisci: The basic science of articular cartilage: Articular cartilage and osteoarthritis. Synovial fluid and synovial membrane mesenchymal stem cells: Stem Cell Res Ther. Lubricin is a product of megakaryocyte stimulating factor gene expression by human synovial fibroblasts. The biology of Lubricin: The role of synovitis in osteoarthritis pathogenesis. Evidence that meniscus damage may be a component of osteoarthritis: The role of innate immunity in osteoarthritis: Bone remodelling in osteoarthritis.

Subchondral bone plate thickening precedes chondrocyte apoptosis and cartilage degradation in spontaneous animal models of osteoarthritis. Int J Mol Sci. Mechanical overload induces VEGF in cartilage discs via hypoxia-inducible factor. The role of varus and valgus alignment in the initial development of knee cartilage damage by MRI: Knee malalignment is associated with an increased risk for incident and enlarging bone marrow lesions in the more loaded compartments: Pathogenesis and management of pain in osteoarthritis. Towards a mechanism-based approach to pain management in osteoarthritis.

Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-kappaB in human osteoarthritis chondrocytes. Rheumatology Oxford ; 50 5: Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Obesity and osteoarthritis, more than just wear and tear: Rheumatology Oxford ; 54 4: Biologic basis of osteoarthritis: The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the horse.

In another study, airway and parenchymal neutrophilia, increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size, were reported [ 69 ]. Moreover, tracheal responsiveness TR to different stimuli is observed not only in asthmatic animals but also in animals exposed to CS [ — ]. This parameter was assessed in some of COPD animal models, in vivo or in vitro. In vivo evaluation of TR has been usually examined by measurement of enhanced pause Penh using whole-body plethysmograph after inhalation of increasing doses of methacholine Mch aerosol [ 31 ]. AHR was assessed by methacholine challenge and measurement of Penh using whole body plethysmography in CS-exposed mice.

The main indicator of airway obstruction, measured as Penh, shows a strong correlation with airway resistance measured using standard procedures [ 31 , ] and was calculated from the chamber—pressure—time curve. In several in vitro studies, tracheal responsiveness to Mch, histamine and isoprenaline was examined using cumulative concentrations-response curve of the corresponding agent and determination of EC 50 [ 52 , 54 , 55 , 57 , , ].

In a study, the tracheal muscle responses of a guinea pig model of COPD induced by CS to cumulative concentrations of histamine 0. In addition, concentration-response curves for isoprenaline in guinea pigs exposed to CS were also constructed by repeated administration of isoprenaline and EC 50 was determined [ 55 ]. Similarly, tracheal responsiveness to Mch was also measured in tracheal smooth muscle by assessing the contraction induced by each concentration of Mch in proportion to the maximum contraction obtained by the final concentration of Mch in an animal model of CS-induced COPD [ 52 , 56 , 58 ].

They release several inflammatory mediators and tissue-degrading enzymes which can orchestrate tissue destruction and chronic inflammation [ 10 , , — ]. Increased total inflammatory cell counts were reported in BAL of animal models of COPD which were mostly due to an increase in macrophages and neutrophils counts [ 33 , 64 ]. Increased total leukocytes, macrophages, neutrophils and lymphocytes in BAL of rats after exposure to tobacco smoke were also reported [ 39 , 41 , 42 ]. Inflammatory cells and mediators in the blood and lung lavage of different animal models of COPD.

Several inflammatory mediators are involved in COPD pathogenesis [ 10 , ]. In addition, Feizpour et al. There is an enormous diversity of methods by which a study on COPD in animals can be done. Thus, there is a need for a standard protocol, which defines parameters to be evaluated and procedures e. In the present review, information regarding induction of experimental models of COPD in different animals, various methods used for this purpose, and different parameters that should be measured, was provided.

This essential information is valuable for designing appropriate studies in future investigations on COPD. All authors read and approved the final manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Mohammad Hossein Boskabady, Phone: Mohammad Reza Khazdair, Email: National Center for Biotechnology Information , U. Journal List Tob Induc Dis v. Published online May 2. Author information Article notes Copyright and License information Disclaimer. Received Nov 19; Accepted Apr This article has been cited by other articles in PMC.

Associated Data Data Availability Statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study It is a review article. Abstract Introduction Chronic obstructive pulmonary disease COPD is a progressive disorder that makes the breathing difficult and is characterized by pathological conditions ranging from chronic inflammation to tissue proteolysis. Results According to the reviewed articles, animal models of COPD are mainly induced in mice, guinea pigs and rats. Conclusion The present review provides various methods used for induction of animal models of COPD, different animals used mainly mice, guinea pigs and rats and measured parameters.

Chronic obstructive pulmonary disease, Emphysema, Animal models, Methods, Inflammation, Lung pathology, Airway responsiveness, Cigarette smoke. Background Chronic obstructive pulmonary disease COPD is a major cause of morbidity and mortality throughout the world and is characterized by chronic airway inflammation, mucus hypersecretion, airway remodeling, and emphysema, leading to reduced lung function and breathlessness [ 1 — 4 ]. Inclusion and exclusion criteria Articles were included if they: Management of search results The search results were checked and included papers were reviewed by authors.

Table 1 Different method used for induction of animal model of COPD and various measured parameters in each model. Animal Method Measured parameters Ref. Open in a separate window. Rats Rats are also used as animal models of COPD [ 10 , 24 ], but they are known as a poor model [ 16 , 35 ], because these animals seem to be relatively resistant to development of COPD [ 10 , 16 , 24 ]. Guinea pigs Guinea pigs are suitable species that are commonly used in COPD studies [ 12 , 43 — 46 ]. Canine Dog Dogs have been extensively used as a model of asthma and COPD [ 59 ], because the pathology and pathophysiology of chronic bronchitis and emphysema after exposure to CS in dogs are similar to humans [ 59 — 61 ].

Monkey Another appropriate animal model for investigation of mechanisms underlying allergic airways diseases and COPD, is non-human primates. Mice Investigations indicated that exposure of mice to inhaled LPS leads to emphysema-like changes which persisted for up to 4 weeks [ 74 , 77 ]. Elastase Elastase is a proteolytic enzyme, which is released by activated neutrophils in the lungs and leads to breakdown of alveolar tissue and emphysema [ 9 , 83 ]. Mice A mouse model of COPD using elastase instillation could be produced by intranasal exposure to 1.

Other models Other agents have also been used to induce airway inflammation injury. Measured parameters Pathological changes A main characteristic of COPD is airflow obstruction which is mostly irreversible. Mice Chronic inflammation, increased cellular infiltration in the lung parenchyma, increased numbers of mucus-secreting goblet cells, thickening of airway epithelium and alveolar enlargement as well as airway remodeling in mouse models of CS-induced COPD were observed [ 1 ].

Rats Increased bronchiole and arteriole wall thickness, bronchiole stenosis, increased alveolar size were shown in a rat model of COPD [ 2 ]. Guinea pigs Baarsma et al. In vivo measurement of TR In vivo evaluation of TR has been usually examined by measurement of enhanced pause Penh using whole-body plethysmograph after inhalation of increasing doses of methacholine Mch aerosol [ 31 ].

Mice AHR was assessed by methacholine challenge and measurement of Penh using whole body plethysmography in CS-exposed mice. In vitro measurement of TR In several in vitro studies, tracheal responsiveness to Mch, histamine and isoprenaline was examined using cumulative concentrations-response curve of the corresponding agent and determination of EC 50 [ 52 , 54 , 55 , 57 , , ]. Guinea pigs In a study, the tracheal muscle responses of a guinea pig model of COPD induced by CS to cumulative concentrations of histamine 0. Table 3 Inflammatory cells and mediators in the blood and lung lavage of different animal models of COPD.

Inflammatory mediators and cytokines Several inflammatory mediators are involved in COPD pathogenesis [ 10 , ]. Mice Duan et al. Conclusion There is an enormous diversity of methods by which a study on COPD in animals can be done. Acknowledgements Not applicable It is a review article. Funding There was not financial support in this article.

Availability of data and materials Data sharing not applicable to this article as no datasets were generated or analyzed during the current study It is a review article. Competing interests The authors declare that they have no competing interests. Consent for publication Not applicable It is a review article. Ethics approval and consent to participate Not applicable It is a review article.

Contributor Information Vahideh Ghorani, Email: A new short-term mouse model of chronic obstructive pulmonary disease identifies a role for mast cell tryptase in pathogenesis. J Allergy Clin Immunol. A rat model for stable chronic obstructive pulmonary disease induced by cigarette smoke inhalation and repetitive bacterial infection. Models for COPD involving cigarette smoke.

Drug Discov Today Dis Models. Murine models of COPD. Animal models of asthma and chronic obstructive pulmonary disease. Wright JL, Churg A. Animal models of COPD: Cigarette smoke exposure as a model of inflammation associated with COPD. Modelling COPD in mice. Inflammation and remodelling in experimental models of COPD.

Models of chronic obstructive pulmonary disease. Mortaz E, Adcock IA. In vivo models of lung disease. Lung diseases - selected state of the art Reviews, InTech. The many faces of airway inflammation: Cigarette smoke drives small airway remodeling by induction of growth factors in the airway wall. Animal models of chronic obstructive pulmonary disease. Airway remodeling in the smoke exposed guinea pig model.

Mechanisms of cigarette smoke-induced COPD: Animal models of cigarette smoke-induced COPD. Animal models of cigarette smoke-induced chronic obstructive pulmonary disease. The composition of cigarette smoke determines inflammatory cell recruitment to the lung in COPD mouse models. Mallia P, Johnston SL. Mechanisms and experimental models of chronic obstructive pulmonary disease exacerbations. Proc Am Thorac Soc. Cigarette smoke exposure produces more evidence of emphysema in B6C3F1 mice than in F rats.

In vitro models of chronic obstructive pulmonary disease COPD. The ion channel transient receptor potential melastatin-2 does not play a role in inflammatory mouse models of chronic obstructive pulmonary diseases. Chronic cigarette smoke exposure primes NK cell activation in a mouse model of chronic obstructive pulmonary disease. SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice.

Detection of lung dysfunction using ventilation and perfusion SPECT in a mouse model of chronic cigarette smoke exposure. Cigarette smoke-induced airway hyperresponsiveness is not dependent on elevated immunoglobulin and eosinophilic inflammation in a mouse model of allergic airway disease. A short-term model of COPD identifies a role for mast cell tryptase.

Thioredoxin-1 protects against neutrophilic inflammation and emphysema progression in a mouse model of chronic obstructive pulmonary disease exacerbation. Comprehensive gene expression profiling of rat lung reveals distinct acute and chronic responses to cigarette smoke inhalation. A new experimental model of cigarette smoke-induced emphysema in Wistar rats. Simvastatin mitigates functional and structural impairment of lung and right ventricle in a rat model of cigarette smoke-induced COPD.

Int J Clin Exp Pathol. Leukocytes are recruited through the bronchial circulation to the lung in a spontaneously hypertensive rat model of COPD. Basis for an Alternative Animal Model. Attenuation of tobacco smoke-induced lung inflammation by treatment with a soluble epoxide hydrolase inhibitor. Development and characterization of a rat model of chronic obstructive pulmonary disease COPD induced by sidestream cigarette smoke. Modeling asthma and COPD in animals: Am Rev Respir Dis.

Bronchopulmonary dysplasia and emphysema: Canning BJ, Chou Y. Using guinea pigs in studies relevant to asthma and COPD. Characterisation of guinea pig precision-cut lung slices: Is the guinea pig trachea a good in vitro model of human large and central airways? Comparison on leukotriene-, methacholine-, histamine-and antigen-induced contractions. J Pharmacol Exp Ther.

An ultrastructural study of the tracheal epithelium of the guinea-pig with special reference to the ciliary structure.

Animal models of osteoarthritis: classification, update, and measurement of outcomes

The effect of adipose derived stromal cells on oxidative stress level, lung emphysema and white blood cells of guinea pigs model of chronic obstructive pulmonary disease. The effect of carvacrol on systemic inflammation in guinea pigs model of COPD induced by cigarette smoke exposure. Tracheal responsivness to methacholine and muscarinic receptor blockade by atropine in animal model of COPD.

Boskabady M, Kiani S. The effect of exposure of guinea pig to cigarette smoke and their sensitization in tracheal responsiveness to histamine and histamine receptor H 1 blockade by chlorpheniramine. Nigella sativa pretreatment in guinea pigs exposed to cigarette smoke modulates in vitro tracheal responsiveness. Iran Red Crescent Med J. Canine models of asthma and COPD. Emphysema produced in dogs by cigarette smoking.

Morphologic alterations induced by short-term cigarette smoking. The non-human primate as a model for studying COPD and asthma. Effects of environmental tobacco smoke exposure on pulmonary immune response in infant monkeys. Animal models of pulmonary emphysema: Bacterial endotoxin is an active component of cigarette smoke. Endotoxin and occupational airway disease. Curr Opin Allergy Clin Immunol. Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD.

Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Inhibition of experimental acute pulmonary inflammation by pirfenidone. Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: Chronic LPS inhalation causes emphysema-like changes in mouse lung that are associated with apoptosis. Goblet cell hyperplasia, airway function, and leukocyte infiltration after chronic lipopolysaccharide exposure in conscious Guinea pigs: Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology.

Elastase-and LPS-exposed mice display altered responses to rhinovirus infection. MR imaging and targeting of a specific alveolar macrophage subpopulation in LPS-induced COPD animal model using antibody-conjugated magnetic nanoparticles. Exposing rodents to a combination of tobacco smoke and lipopolysaccharide results in an exaggerated inflammatory response in the lung. Effects on lung remodeling and pathology.

Current Assessment of the Protease-Antiprotease Hypothesis 1—3. An Acad Bras Cienc. Animal Models of Emphysema 1—3. The first two centuries and beyond. A historial overview, with suggestions for future research: An animal model for lung volume reduction therapy of pulmonary emphysema.