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Supplement: Countermeasures to Laminitis: Countermeasures to Laminitis

Countermeasures for Pasture-Associated Laminitis in Ponies and Horses^1,2

Patricia Harris^*,3, Simon R. Bailey, Jonathan Elliott and Annette Longland^**

^* Equine Studies Group, WALTHAM Centre for Pet Nutrition, Department of Veterinary Basic Sciences, Royal Veterinary College, London, UK and ^** Institute of Grassland and Environmental Research, Plas Gogerddan, Aberystwyth, UK

³ To whom correspondence should be addressed. E-mail: pat.harris{at}eu.effem.com.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
Laminitis occurs throughout the world in horses and ponies and has major welfare implications. It is obviously important to be able to recognize and treat the condition in its early stages so that pain and suffering are kept to a minimum. However, ideally it would be preferred to be able to recommend certain interventions/countermeasures that avoid or prevent the condition from occurring in the first place. Because pasture-associated laminitis occurs with grass consumption, one obvious way to avoid the condition is to prevent access to pasture and to feed forage alternatives that are known to be low in rapidly fermentable material. For the majority of horses, total restriction is not always a viable or desired option for financial, welfare, and health reasons. It also may not be necessary for those animals that are not predisposed to laminitis. This review discusses the possible countermeasures that could be considered now and in the future in the following 7 key areas: 1) Identifying animals predisposed to the condition; 2) Limiting development of insulin resistance; 3) Avoiding high intakes of rapidly fermentable material; 4) Preventing/reducing the formation and absorption of the various "triggering factors"; 5) Reducing/preventing oxidative damage; 6) Preventing/reducing matrix metalloproteinase activity; and 7) Preventing changes in blood flow. It is unfortunate that little or no hard data exist at present on effective countermeasures, only mechanistic evidence for avoiding risk factors. However, there is much to gain, and research in this area is urgently required.

Laminitis has plagued domesticated horses since the beginning of recorded history (10). According to a general survey in the United States, apart from colic, laminitis is the most common reason for a horse or pony to be presented for veterinary treatment (11); 13% of horse owners/operations reported problems with laminitis in their horses over the previous 12 mo with death or euthanasia in 5% of those affected by laminitis. Higher fatalities were reported in veterinary teaching hospitals and referral center surveys; for example, 20% died or were euthanized in one such survey (12), which may reflect the severity and nature of the cases evaluated. A large study in the UK found a prevalence of 7.1% and estimated that 8000 horses suffered from laminitis each year; of these, 600 were euthanized because of this condition and 1300 horses were left permanently unsound, thus contributing to the pool of >16,500 chronically laminitic animals (13). Although laminitis is truly a global condition of horses and ponies with major welfare implications, we still do not fully understand aspects of this naturally occurring condition. This lack of understanding ranges from its epidemiology to its pathogenesis (1,10) e.g., despite anecdotal reports, reviews, and surveys such as that carried out in the United States (11), which stated that the most commonly perceived cause of laminitis is grazing "lush" pasture, very few in-depth epidemiologic studies have in fact been undertaken, as reviewed by Alford et al. (14). Those studies that were conducted often did not have sufficient numbers to allow real definition of the risk factors. Information, therefore, tends to be based on anecdotal clinical views, e.g., fat ponies are most susceptible.

However, research has been conducted confirming, for example, that overfeeding of cereals can reproducibly cause laminitis (15,16), as can bolus feeding of a commercial inulin-type fructan (7,17) and the feeding of black walnut extract (18,19). Research has concentrated primarily on such models and tried, quite logically, to understand how such manipulations result in laminitis, especially because the prodromal stage of the naturally occurring condition is not clinically recognizable in the field. In addition, by the time that clinical signs are present, a number of secondary processes have become involved, which distort the picture; these include inflammation resulting from ischemia and reperfusion injury, MMP induction and activation, plus physical trauma to secondary lamellae as they begin to separate from the basement membrane. However, the majority of animals that suffer from laminitis today have not consumed cereals ad libitum [7% of cases in the USDA-National Animal Health Monitoring System (NAHMS) 2000 study (11) were thought to be due to grain overload] or ingested large amounts of pure fructans as a bolus. Furthermore, not all of a group of ponies or horses out on a particular pasture will develop laminitis. Thus, we lack the scientific information that links the research work with the situation in the field.

Despite the lack of published scientific studies, most veterinarians and horse owners would agree that the majority of cases of laminitis occur in animals out at pasture. This was confirmed by the UK survey (13,20) conducted in the mid 1990s (61% of animals were kept out at grass before an attack, 30% on a combined system, and 9% stabled), and in the US survey [45% of cases (11)]; therefore, this paper concentrates on pasture-associated laminitis.

Possible sequence of events in pasture-associated laminitis

Turning certain ponies or horses out onto "lush" (i.e., green, actively photosynthetic) or "stressed" (i.e., environmental conditions are suboptimal for growth) pastures (21) especially in the spring and autumn is thought to be a common predisposing factor, and there is some evidence to support this. In the USDA-NAHMS 2000 survey (11), for example, laminitis accounted for 20% of the hoof or foot problems in the winter but 40% in the spring. Currently it is thought that the high levels of water-soluble carbohydrates (WSC, which include the simple sugars as well as the more complex storage carbohydrates, fructans) and/or starch, may be involved in this process (21). As noted by Bailey et al. (1) "fructans, a group of fructooligosaccharides of varying molecular size and branching structure are produced as a storage carbohydrate in grasses and levels increase under climatic conditions favoring photosynthesis over growth. These conditions (bright sunshine during the day with cool nights) are similar to those associated with increased incidence of pasture laminitis" (22–24). It is thought that, like other mammals, horses do not have the necessary enzymes to digest fructans directly within the small intestine (25). Fructans therefore pass into the hindgut where they are readily fermented, in a manner similar to starch that escapes digestion in the small intestine (e.g., after the ingestion of too large a cereal-based meal or high levels of starch in certain plants) (26). A schematic diagram of the possible consequences of such an event is given in Figure 1. It is important to note that although much current research concentrates on the role of fructans in pasture-associated laminitis, other potentially rapidly fermentable carbohydrates (sugars and starch) may be as important or possibly more important in some cases. In addition, it should be noted that there may be other specific causes of pasture-associated laminitis, for example, secondary to the ingestion of endophyte (Neotyphodium coenophialum)-infected Tall Fescue (Festuca arundinaceae) (27). However, even here, it is possible that there is a link with the mechanisms of laminitis pathophysiology shown in Fig. 1, because certain ergot alkaloids (e.g., ergotamine) may cause digital vasoconstriction by activating 5-hydroxytryptamine (5-HT) receptors (Bailey, unpublished data).

View larger version (49K): [in this window] [in a new window]   FIGURE 1  Illustration of the possible sequence of events in cereal overload or grass-associated laminitis and the potential influence of insulin resistance and raised cortisol levels. The 7 key countermeasure target areas discussed in the text are indicated.

In this context, we should consider countermeasures that include both passive avoidance, meaning "keeping out of the way," and active prevention, meaning "to keep from happening especially by taking precautionary action." Ideally, this would indicate countermeasures that are effective before there is induction of the pathological processes that lead to separation. However, for us to consider appropriate and effective countermeasures for pasture-associated laminitis, we have to understand why particular pastures result in laminitis in certain individuals at certain times. Only once this is fully understood can we develop appropriate countermeasures to help avoid and prevent laminitis. Figure 1 provides an overview of possible ways in which pasture intake may trigger laminitis, and gives an idea of potential applications of countermeasures according to our current state of knowledge. However, as mentioned above, there is still much to confirm and to understand.

Because pasture-associated laminitis occurs at pasture, then an obvious way to avoid the condition is to prevent access to pasture and to feed forage alternatives that are low in rapidly fermentable material. For the majority of horses, total restriction is not always a viable or desirable option for financial, welfare, and health reasons (28). It may also not be necessary for those animals that are not predisposed to this condition. Ideally, then, the first stage in our countermeasures would be to determine whether an individual animal had an increased risk of laminitis.

Key area 1: Identifying animals predisposed to laminitis

There may be breed, age, and sex effects in the incidence of laminitis (14). Certainly it is generally accepted that ponies are more commonly affected by laminitis than horses (14,24,29,30). It was also suggested that thoroughbreds may have a reduced susceptibility although this may be linked more to activity levels than breed; more work is required to confirm this (14,30). Ponies and horses that have been previously affected with laminitis or are affected with certain other diseases (e.g., pituitary pars intermedia dysfunction) are at increased risk of laminitis (31).

Perhaps a more interesting question is why certain apparently healthy individuals may be affected, whereas others of the same age, breed, and gender following the same management regimen show no signs. This is the subject of much interest at present. Individual variations in gastrointestinal function or tissue sensitivity to trigger factors, e.g., peripheral blood vessel responsiveness may play a role (1) as may the level of insulin resistance. Recent work has also begun to examine the genetic aspects in more detail.

    Individual differences in peripheral blood vessel responsiveness. There is evidence that vasoconstriction occurs in the prodromal phase of laminitis, particularly on the venous side of the circulation (32). Among the more potent endogenous vasoconstrictors are 5-HT, endothelin, and thromboxane (TX). Vasoactive amines may be released from the large intestine into the circulation, and displace 5-HT from platelets (33). Platelet activation in turn has been implicated in the pathophysiology of laminitis (34,35), and interestingly, it appears that more TXA₂ (a vasoconstrictor mediator) is produced after activation of platelets in vitro in ponies than horses (36), which may be a factor in the increased risk of laminitis in ponies. It is also possible that some individuals are more responsive than others; however, no work has been conducted in this area.

Endothelial dysfunction is a common sequel to hyperinsulinemia because chronic insulin exposure leads, for example, to downregulation of nitric oxide production and increased production of endothelin-1 (37), which itself has been implicated in the pathophysiology of laminitis (38,39). Increased concentrations of homocysteine have been linked with endothelial dysfunction (by reducing nitric oxide production) and an increased risk of cardiovascular disease in humans (40). It was therefore hypothesized that elevated levels might predispose to laminitis. However, this was not supported in a recent study (41), although the work did show that homocysteine (which is formed by the metabolism of methionine, a sulfur-containing amino acid, commonly included in supplements to support hoof health) could interfere with endothelial cell function at physiologically relevant concentrations (41). This suggests that management regimens that lead to significant increases in plasma homocysteine concentrations should be avoided in ponies predisposed to laminitis.

    Role of genetic predisposition. This is a rapidly expanding area and may involve individual genetic abnormalities as well as group abnormalities as outlined below. Recently, for example, it was shown that laminitis in a foal resulted from disruption or damage to a single molecule of the hemidesmosome adhesion complex of the inner hoof wall lamellae, believed to be the result of an inherited recessive gene responsible for failure to express plectin protein (42). An increased risk of laminitis in Belgian foals with mechanobullous disease (epidermolysis bullosa) was also demonstrated (43).

In another study, pedigrees from 257 Welsh and Dartmoor ponies born between 1933 and 2002 from an inbred herd were analyzed with respect to the incidence of grass laminitis. Of these, 37% were reported to have experienced some observable signs, and nearly half had a parent that was also recorded as a laminitic; all reported cases, with 1 exception, were mares. However, the lone male case was a stallion whose daughters all showed signs of laminitis (44). These findings suggest a possible genetic component, but further work is required within this group and other unrelated animals prone to the condition to determine how these findings may be applied more generally.

A major aim for any countermeasure strategy, however, would be to be able to identify apparently healthy ponies with a genetic predisposition for laminitis from their genotype, so that they can be managed appropriately.

    Role of individual differences in gastrointestinal tract processes. Recent work from Germany (45) showed that Jerusalem artichoke (contains inulin, a fructan) was more effective in stimulating microbial activity (as assessed by the rise in hydrogen and methane exhalation postingestion) than a meal of oats providing the same amount of hydrolyzable carbohydrates. Interestingly, within this study, there were large individual differences, which could be linked to individual levels of predisposition to gastrointestinal disturbances and toxin production.

    Role of condition score, exercise, and the individual on insulin resistance. Glucose is important in maintaining lamellar integrity and was shown to be essential for the viability of hoof explants in culture. Culture without glucose or inhibition of glycolysis causes basement membrane zone separation under tension (46); the authors suggested that high circulating corticosteroid levels and/or inhibition of insulin activity could result in such an effect. It is possible that in the insulin-resistant state, glucose transporters are downregulated in the lamellar tissues and therefore glucose entry into the epithelial cells may be impaired, as was demonstrated in chronic laminitis (47). It is well-recognized, although again there are few objective data, that obese animals especially ponies are more prone to laminitis (14); this may be linked in part to mechanical trauma due to the increased load. However, it is likely that the risk for laminitis in obese horses (condition score >7 on a 9-point scale) is more appropriately attributed to the development of insulin resistance (30,48–50). The "syndrome" of obesity, insulin resistance, and laminitis in mature horses has been referred to as either "peripheral Cushing's syndrome" or an equine "metabolic syndrome" (51,52), although this description has been disputed (49). Insulin sensitivity has also been found to be affected by diet; large fluctuations in glucose and insulin after meals high in sugar may supply inappropriate signals of energy availability to the glucose regulatory system, altering insulin sensitivity of the tissues (53,54). In Thoroughbred weanlings adapted to a sugar and starch diet, insulin sensitivity was lower compared with weanlings adapted to a feed rich in fat and fiber (55). Mature Thoroughbred geldings with normal body condition scores tended to have decreased insulin sensitivity when adapted to a sugar- and starch-based diet (56). It was suggested that there may be a progression of insulin resistance in laminitis-prone ponies from compensated insulin resistance (i.e., insulin sensitivity greatly decreased but compensated for by increased insulin secretion), as a predisposing factor in healthy but genetically predisposed ponies, through to a decompensated insulin resistance later in the course of the disease (57).

Specific breeds that were suggested to have an increased risk of developing insulin resistance include pony breeds in general, Morgan Horses, domesticated Spanish mustangs, European warmbloods, and American saddlebreds (30,52); however, to the authors' knowledge, there is insufficient epidemiologic information to confirm whether there is an increased susceptibility to laminitis in these breeds.

In the survey carried out by Alford et al. (14), a significantly higher proportion of acute laminitis cases than controls occurred in the "no-regular exercise" category, and the authors questioned "if regular exercise is protective against laminitis, is it merely because it decreases obesity—or does it mediate through other physiological effects." It is certainly well-recognized in humans that exercise and exercise training have numerous beneficial effects including those on glucose homeostasis and enhanced insulin sensitivity (58); similar effects are thought to occur in horses (59).

Key area 2: Limiting the development of insulin resistance

Although this may be involved with an individual predisposition to laminitis, it is a sufficiently important area to be given its own section. Certainly it would seem advisable to consider countermeasures that aim to avoid or prevent both chronic insulin insensitivity (due to adaptation to glucose-yielding carbohydrates) and acute insulin resistance following rapid fermentation of sugar, starch, and fructan. Countermeasures to reduce the risk of insulin resistance in certain breeds could include modifying the diet of healthy horses by replacing starch- and sugar-based diets safely with appropriately formulated fat- and fiber-based feeds that produce a low glycemic and insulinemic response and avoid the insulin insensitivity that develops during chronic adaptation to sweet feed (26,60). The development of rapid and easy methods to determine insulin resistance reliably would help considerably in this aspect.

Encouraging owners to monitor body weight (BW) and condition score more regularly (61) to try and maintain animals at a more optimal weight (4–6 on a 9-point scale) and avoid obesity (62) together with maintaining regular exercise, wherever possible (14,59), would be relatively simple countermeasures that could be implemented.

Key area 3: Avoiding high intakes of rapidly fermentable material

For those animals identified as being at high risk of developing laminitis, a less radical solution than totally restricting their access to pasture, would be to restrict access at high-risk times of the year and the day.

This requires the identification and more detailed description of risk factors that result in the pasture containing high levels of rapidly fermentable material, i.e., when is the best time to restrict access to pasture to reduce the risk of Laminitis (21)? Such information should enable the development and testing of innovative pasture and feeding management strategies that avoid these risk factors, hence reducing the incidence of laminitis. As mentioned above, few studies even looked at the effect of time of year, but several in the United States and one in the UK suggested an increased risk in May (US) and May/June (UK) (11,14,20). However, not all studies showed a seasonal effect (63).

Current thinking, however, is that laminitis could be largely avoided, especially in genetically predisposed animals, by grazing when the levels of starch, sugar, and fructans were low. However, this could be difficult to predict because these factors may vary from season to season, location to location, and within a location during the particular day, according to plant species, field topography, and grazing patterns of individual animals. Further work in this area is clearly warranted (21). There is also limited information available regarding the amounts of pasture that different breeds and in particular the pony may be able to ingest either when turned out for 24 h or for only a short period of time (as is often undertaken in the management of ponies prone to laminitis), although some preliminary data are now available (21,64).

It was shown that a bolus of fructan between 7.5 and 12.5 g/kg BW (the equivalent of 5 kg to a 500-kg horse in 1 meal) can reliably produce laminitis (7) even in a breed not believed to be prone to the condition. But it has been questioned whether grazing animals would ever reach the "threshold" amount of rapidly fermentable carbohydrate required to initiate the sequence of events under normal grazing conditions. However, this may be a difficult question to answer fully because the threshold levels determined under controlled conditions may be very different from what occurs naturally in an individual predisposed to the condition. However, there is ongoing research in this area, and the concentration-dependent effect of a fructan (inulin) on cecal pH was determined recently using an in vitro model (65). In a linked in vivo study in ponies, in which controlled amounts of inulin were fed to normal ponies as well as ponies predisposed to laminitis, significant decreases in fecal pH were found in particular when fructan was added at 3 g/kg BW, although there were no differences in those prone to laminitis compared with controls (65). Although not the subject of this review, there is work to suggest that even in grain-adapted horses and ponies, 2.1 g of rapidly fermentable carbohydrate/kg BW in the form of starch was sufficient to elicit unfavorable changes in intracecal fermentation in ponies (26,66).

Current advice regarding avoiding high intakes of rapidly fermentable material, while at pasture, includes the following: due to the highly variable and unpredictable nature of fructan accumulation in pasture (23) animals predisposed to laminitis should preferably be denied access to grass pastures during the growing season. However, if some grazing is unavoidable, turn animals out very late at night or very early in the morning, removing them from pasture by mid-morning at the latest because fructan levels are likely to be at their lowest late at night to early morning (67). Mature stemmy grasses may contain more fructan because it is stored in the stem (68); therefore, avoid pastures that have not been managed properly by regular grazing or cutting. At the change from vegetative (i.e., leaf growth and expansion) to reproductive development (ear emergence), WSC/fructan levels are likely to be high (67); therefore, avoid turning horses out to pasture during the late spring when WSC/fructan levels are rising. Cold temperatures will reduce grass growth, resulting in the accumulation of fructan (69). Therefore, do not turn horses out onto pasture that has been exposed to low temperatures in conjunction with bright sunlight, such as occurs in the autumn after the autumn flush of growth, or bright, cool winter days. Because fructan is stored predominantly in the stem (68), do not allow animals to graze on recently cut stubble. Finally, consider allowing animals to graze on pastures that contain timothy and cocksfoot because these grass species tend to produce lower levels of WSC and fructans with a higher molecular weight than ryegrass; they may be fermented less rapidly (69,70) and may be less likely to cause hindgut acidosis (70). This advice, however, may have to be adjusted to the local environment and grass types (21). Grazing muzzles may be useful providing they are fitted and used appropriately, e.g., regular access to water is provided. But changes in the dynamics between animals within a group situation must be taken into consideration when using such devices.

Dietary and therapeutic agents that may prevent laminitis

Again, there have been few if any controlled trials that tested interventions with feeds, dietary supplements, and feed additives with respect to laminitis prevention. There has also been little work reported on drugs that might work on a long-term basis to prevent laminitis.

Two types of agent could be considered: 1) those that act once clinical signs are seen to minimize the severity of the condition, prevent the separation of the pedal bone from the lamellar interface, and improve recovery rates; and 2) those that could be given safely, maybe at key times of the year as discussed above, to reduce the risk of the condition even starting. It is this second group that will be considered further; as illustrated in Figure 1, there are a number of avenues that could be approached.

Key area 4: Preventing/reducing formation and absorption of the various "triggering factors"

Included in this section would be hind gut buffers (that help prevent or limit any decrease in the large intestine pH) as well as agents that prevent the formation of amines and the various exotoxins, e.g., thermolysin from Streptococcus bovis (71); at present, however, the most likely avenue to follow is to prevent their formation by reducing the proliferation of the lactate- producing saccharolytic microflora. This would also have the additional benefit of reducing the production of endotoxin, another putative trigger factor. Reducing the rate of fermentation (so that excessive lactic acid is not produced) may be achieved, as discussed above, by reducing the intake of rapidly fermentable material (especially fructans, starches, or sugars) in the first place or by providing fructans of a longer chain length so that they are fermented more slowly. Influencing the microflora or pH within the gastrointestinal tract, so that there is less likelihood of production of the various "trigger factors," is also a possibility.

The influx of rapidly fermentable carbohydrate [starch, water soluble carbohydrates: sugars and/or fructan (21)] primarily into the large intestine results in overgrowth of gram-positive bacteria and a decrease in gram-negative bacteria (16,26,72,73). It was shown that elevated levels of WSC in grasses may substantially increase lactate production by colonic microbes (74). The streptogramin antibiotic virginiamycin, for example, "has been used and marketed to prevent pasture-induced laminitis by preventing the overgrowth of gram positive cecal bacteria" (1) based on work done in Australia, which suggested that predosing with virginiamycin prevented the development of laminitis after administration of a wheat slurry (75). It was also shown to significantly reduce the production of vasoactive amines in vitro when cecal contents were cultured with starch, in particular, as well as a commercial fructan [inulin; (76)] to a lesser degree. However, virginiamycin is available only in Europe under special license for a named client (it was banned for use as a growth promoter in pigs and poultry in the European Union due to concerns over antibiotic resistance); anecdotally, it is not effective in all cases. There has been limited work on other agents that may inhibit the growth of the gram-positive bacteria. A steroidal saponin was shown in other studies to have the potential to inhibit the growth of S. bovis but had no effect at the doses used in the in vitro model to evaluate the effects of virginiamycin (76). Interestingly, in that study, although the addition of calcium hydrogen phosphate (a buffer previously shown to moderate the fall in pH associated with the fermentation of fructans in the rat cecum) moderated the changes in pH, it did not affect the production of the monoamines. Obviously, the use of other antibiotics that are less selective or are bactericidal in nature could be counterproductive and lead to other problems.

Key area 5: Reducing oxidative damage

Oxidative damage may play a role in laminitis because increased free radical formation was suggested to occur as a result of changes in glucose/insulin metabolism and the development of insulin resistance; free radicals produced by glucose autooxidation may cause oxidative damage to the vascular endothelium, and reperfusion injury may result from the sudden generation of oxygen free radicals (1,60,77). Neutrophil adherence to the damaged/activated endothelium and their subsequent migration into the tissues may be a further source of superoxide radicals and also MMP-9 (78). Interestingly MMP-9 production by vascular endothelial cells is increased under high-glucose conditions, and this glucotoxic effect can be reversed under certain conditions by antioxidant supplementation [vitamin C (79)] at least in humans.

A recent study by Neville et al. (80) suggested that ponies with chronic laminitis may have higher levels of markers of lipid peroxidation as measured by urinary thiobarbituric acid reactive substances than ponies who do not suffer from laminitis. The exact cause of this increase in free radical production is yet to be determined, but it is likely to be multifactorial (60). It is clear that further investigation is warranted to determine the precise role of free radicals in the pathogenesis of laminitis, and work is required to determine whether antioxidant supplementation (what, when, and for how long) may be of any value.

Key area 6: Preventing increased MMP activity

MMP activation (in particular MMP-2 and MMP-9) was shown to occur in laminitis (6–8,81), and this results in the loss of attachment between the interdigitating dermal and epidermal lamellae, potentially allowing the pedal bone to become displaced. Many factors can induce MMP production/secretion (82) and subsequent activation (83) including a number of bacterial proteases/exotoxins and endotoxins (71,84). Work is currently ongoing to look at possible agents that could be applied either systemically or by local administration that might block activation of these enzymes or inhibit their activity (7,85).

It was suggested that continuously applied cryotherapy may reduce the delivery of the triggering factors [this group believes that hyperperfusion of the digit is responsible for increased delivery of such factors (86,87)], although this may also have the effect of inhibiting MMP activity and perhaps protect against ischemia-reperfusion injury (1).

One of the potential problems with agents that reduce or limit MMP activation is that MMP enzymes are important in normal tissue remodeling in many parts of the body other than the hoof; therefore, such agents should be used perhaps only as a short-term treatment in the acute or developmental (if known) phase of the disease, rather than as a preventative. Alternatively, work is required to understand whether it is possible to target specifically activity at the hoof level. Much more work is warranted in this potentially very promising area.

Key area 7: Preventing changes in blood flow

A number of avenues are or could be explored within this context. For example, it was suggested previously that agents that prevent platelet activation or improve RBC deformability, thereby improving blood flow, may be of value under experimental conditions (35,88); however, more work is required with respect to their efficacy in field situations. Cortisol was shown to independently increase the sensitivity of digital blood vessels to vasoconstrictors such as 5H-T (serotonin) in vitro (89). It is possible that raised cortisol concentrations [due to iatrogenic administration, hyperadrenocorticism (Cushing's syndrome), or general "stress"], by lowering the threshold concentration of the various vasoconstrictor agents required to cause a significant alteration in blood flow, increase the risk of laminitis as illustrated in Figure 1. Tissue-specific cortisol dysregulation was also suggested to play a role (90).

    Vasoactive monoamines. The digital blood vessels, in particular the veins, are extremely sensitive to the effects of some of the monoamines that are produced during rapid fermentation of carbohydrate (91,92) by lactobacilli and S. bovis in particular (73). Recently, the inducible decarboxylase enzyme responsible for the production of tryramine was characterized from Lactobacillus salivarius (commonly found in the cecum of horses) (93), which obviously provides useful information for the future. However, more work is required before it is possible to determine whether amines represent a real countermeasure or therapeutic target.

    Endotoxin. Horses with clinical signs of endotoxemia (systemic inflammatory response syndrome) appear to be more susceptible to laminitis (94). Increased endotoxin was found in the intestinal tract and plasma of horses that developed laminitis after carbohydrate overload, but it does not appear in the plasma in all models of experimental laminitis (18), and most horses with endotoxemia do not develop laminitis. Additionally, direct infusion of endotoxin into the peripheral vasculature was not shown to induce laminitis (95), although clinical signs indicative of laminitis were reported after infusion of endotoxin into the portal circulation (96). It is possible that endotoxin contributes to the cascade of events resulting in laminitis (e.g., activation of platelets to release TX and 5-HT, as demonstrated in vitro (1,97,98), rather than directly causing laminitis per se. Therefore, agents that reduce the effects of endotoxin, including antiplatelet therapy (98), could be of value but may be unlikely to prevent laminitis if given on their own.

    Endothelin. Endothelin is also a very potent vasoconstrictor, especially of veins, and increased expression was observed in laminitis (38), although again it is unclear whether it has a primary or secondary role in laminitis (1). However, it was shown in experimental models that the vasoconstriction in the developmental stages could be reversed using an endothelin receptor antagonist and the increased venous resistance seen postvasoconstriction could be blocked (99,100). Therefore in the future, it is possible that endothelin receptor antagonists or inhibitors of the endothelin-converting enzyme may have a role to play; clearly, further work is warranted.

    Vasodilators. A number of vasodilator substances act to counterbalance the effects of the various vasoconstrictor mediators in the equine digit including nitric oxide and endothelium-derived hyperpolarizing factor (101). However, there does not appear to be any evidence of a deficiency in intrinsic nitric oxide production in laminitis, although i.v. administration of L-arginine (the substrate for nitric oxide production) in 1 horse did result in vasodilation of the foot (102). Topical application of a nitric oxide donor (glyceryl trinitrate) gave clinical improvement in 10 ponies with laminitis (103) with a reduction in blood pressure, although the lack of objective data on blood flow to the sensitive laminae before and after the glyceryl trinitrate treatment limits the conclusions that can be drawn from this study (104). However, other in vitro studies also showed an effect of providing nitric oxide donors after administration of black walnut extract (99), although treatment with glyceryl trinitrate had no effect after development of clinical signs of laminitis in horses following such administration (105). It is also thought that normally the circulatory concentrations of arginine are more than adequate to support nitric oxide production, although it is possible that some disturbance or limitation is involved in certain individuals; again, much more information is required. The effectiveness of topical nitric oxide donors with repeated use may be diminished due to desensitization (1) as well as ineffective absorption into the digital arterial supply (106).

Other possibilities

Other aspects that perhaps could benefit from exploration include the role of agents that counter insulin resistance [pharmacological agents such as the thiazolidinediones or herbs such as cinnamon (93)] and improve peripheral glucose uptake as well as the potential for immunization against certain toxins. There is some preliminary experimental support for the use of some agents in the developmental phase but "field trials examining the effectiveness of these agents in naturally occurring cases will be required to establish their true value in the clinical situation" (1).

In conclusion, it is unfortunate that no hard data on effective countermeasures exist at present, only mechanistic evidence for avoiding risk factors. There are at least 7 key areas that could be targeted, however, and research in these areas is urgently required.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of The WALTHAM International Nutritional Sciences Symposium: Countermeasures to Laminitis held in Washington, DC, September 14, 2005. This conference was supported by The WALTHAM Centre for Pet Nutrition and organized in collaboration with the Virginia Polytechnic Institute and State University. This publication was supported by The WALTHAM Centre for Pet Nutrition. Guest editors for this symposium were D'Ann Finley, Francis A. Kallfelz, James G. Morris, and Quinton R. Rogers. Guest editor disclosure: expenses for the editors to travel to the symposium and honoraria were paid by The WALTHAM Centre for Pet Nutrition.

² Author disclosure: no relationships to disclose.

⁴ Abbreviations used: BW, body weight; 5-HT, 5-hydroxytryptamine; MMP, matrix metalloproteinase; NAHMS; National Animal Health Monitoring System; TX, thromboxane; WSC, water-soluble carbohydrates.

	LITERATURE CITED

TOP ABSTRACT LITERATURE CITED

 

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