Progress towards effective prevention and therapy for laminitis

Authors


The search for an effective means of treating or preventing laminitis has intensified in the last decade, particularly in the aftermath of discoveries that shed light on important differences in the pathophysiology of laminitis under different circumstances. EVJ's virtual issue contains articles that have important implications for the development of effective laminitis therapeutics, as well as new scientific evidence that supports a therapeutic intervention (cryotherapy) with ancient roots.

Is there a common therapeutic target during laminitis development?

It was not long ago that all laminitis, regardless of the underlying cause, was considered to be the result of the same major pathological event, namely ischaemia. Attempts at preventing and treating laminitis through enhancing digital perfusion met with little success. More recently, degradation of the basement membrane and its attachments (possibly by resident and leucocyte-derived proteases) [1-3] and the presence of profound local and systemic inflammation during development [4, 5] have been identified as additional targets for therapeutic intervention: but are they common to the different forms of laminitis that we see clinically?

These major events have been documented experimentally using alimentary carbohydrate-overload models of laminitis, as well as the black walnut extract model, which most closely mimic only those natural disease states that are characterised by sepsis [6]. It is now recognised that the majority of naturally occurring laminitis cases are linked to insulin resistance, and ultimately hyperinsulinaemia [7], and do not necessarily share these same pathways. The original work by Asplin et al. [8] demonstrated that high concentrations of insulin, in the presence of euglycaemia, could induce laminitis experimentally in ponies. Furthermore, Asplin et al. [9] questioned the similarity of the hyperinsulinaemia-induced laminitis lesion to that previously reported with the carbohydrate-overload models: specifically, the ponies demonstrated an absence of extensive basement membrane damage. In this issue, de Laat et al. [10] demonstrated that the lesions in Standardbred horses subjected to hyperinsulinaemia did involve more classic basement membrane separation, citing increased body weight, and therefore enhanced mechanical distraction, as an important difference. Both studies have demonstrated the infiltration of inflammatory cells, albeit as a secondary event.

Although inflammation and basement membrane destruction (presumably by proteases) appear to represent common and logical therapeutic targets in different forms of laminitis, there have been few studies specifically designed to assess these therapeutic avenues. In a study included in this virtual issue, Williams et al. [11] demonstrated that intravenous lidocaine had no effect on systemic and lamellar inflammation in the black walnut extract model, in fact there was some evidence of a pro-inflammatory effect. In contrast, digital hypothermia did exert a profound anti-inflammatory effect during the development of laminitis [12], which may in part explain its preventative action [13, 14]. It is clear that further investigation of therapeutics aimed at controlling inflammation is warranted: as suggested by Leise et al. [5], therapies aimed at more central inflammatory pathways such as signal transduction and transcriptional control are worthy of investigation.

The rationale behind inhibiting basement membrane degradation using targeted anti-protease therapy is more problematic. In a study included in this virtual issue, the contribution of matrix metalloproteinases to basement membrane degradation and detachment has been questioned in the carbohydrate model [15], although other proteases (including ADAMTS-4) were suggested as likely early contributors. Interestingly, new evidence suggests an absence of significant protease activity in laminitis induced by hyperinsulinaemia [16], despite there being evidence of basement membrane separation in this model. The mechanisms leading to basement membrane separation remain unclear and it appears that, at the very least, the proteases do not represent a common target for therapeutic intervention across different forms of laminitis. Loss of hemidesmosomes, the normal epidermal basal cell ‘anchors’ to the basement membrane, does appear to be a phenomenon that is at least common to both the carbohydrate and insulin models of laminitis [17-19]. A failure of glucose supply has been demonstrated as a cause of this in vitro [20, 21]; however, it seems that simple failure of glucose delivery to the lamellar epidermal cells due to insulin resistance is unlikely given their lack of dependence on insulin-mediated glucose transport [22]. It may be that failure of hemidesmosome maintenance/hemidesmosome dissolution is a consequence of any disruption in epidermal basal cell homeostasis, regardless of the inciting cause. In any event, the key to identifying a common therapeutic target related to basement membrane separation lies in determining the cause of hemidesmosome failure.

Although anecdotal evidence suggests that increased body weight, and therefore enhanced mechanical distraction, may be associated with more progressive and profound laminitis, there has, until recently, been no scientific evidence to support this. In a study included in this virtual issue, increased body weight is cited as a contributor to the severity of laminitis induced by hyperinsulinaemia [10] as well as a risk factor for supporting limb laminitis [23]. In the study of Virgin et al. in this virtual issue [23], for every kilogram increase in body weight, the likelihood of supporting limb laminitis increased by 1%. The work of Leise et al. (also in this virtual issue) [24] demonstrates the importance of body weight distribution: in the face of equivocal local inflammatory responses, the forelimbs suffer more marked laminitis than the hindlimbs. The development of strategies aimed at redistributing or relieving body weight during laminitis development may be an overlooked but realistic therapeutic goal: novel sling technology or further development of previously described forced recumbency techniques [25] are potential solutions that are worthy of further investigation.

Prevention is always better than a cure

The study by Visser and Pollitt in this virtual issue [26] presents striking new evidence demonstrating just how early structural changes can occur within the lamellar tissue before the onset of lameness in an experimental model. It follows that in the clinical setting, lamellar pathology is likely to be well established before clinical recognition of the disease. This highlights the importance of a preventative approach: waiting until clinical signs develop will tip the balance in favour of the destructive processes that drive the lamellar tissue towards structural failure. Prevention begins with the identification of horses at risk. Pre-emptive measures to either eliminate risk factors where possible or intervene therapeutically before establishment of the disease can then be instituted. In systemically ill horses, signs of sepsis or endotoxaemia are an established risk factor for laminitis [27] and therefore aggressive therapy aimed at binding circulating endotoxin (polymixin B, plasma) and controlling systemic inflammation (nonsteroidal anti-inflammatory drugs, pentoxifylline) is rational. Continuous cryotherapy of the feet in these cases may prevent or at least ameliorate laminitis as it has done in the experimental setting (see studies in this virtual issue) [13, 14].

The accurate identification of insulin resistance in horses and ponies can allow for timely intervention with preventative therapeutics and changes in management that reduce the risk of laminitis development [28]. New studies are refining simpler, clinically relevant means of identifying insulin resistance and laminitis predisposition: a simple oral glucose response test [29] and the measurement of plasma fructosamine [30] show great promise. In this issue Borer et al. [31] attempted to further categorise ponies, which they found to be inherently insulin resistant, according to their predisposition to develop laminitis based on proxy measurements of insulin sensitivity. Although unable to identify laminitis predisposition in individuals, the approach warrants further investigation in a larger cohort. Pharmaceutical treatments aimed at increasing insulin sensitivity, including metformin [32] and pioglitazone [33], require further investigation before they can be recommended in equine patients. Pre-emptive dietary management and particularly exercise programmes will always be important in successful prevention and even treatment of laminitis in obese insulin-resistant horses [34].

The study by Virgin et al. [23] sheds new light on risk factors for supporting limb laminitis: body weight, duration of cast application and type of cast were implicated. However, besides aggressive management of the primary condition, there is currently little information on which to base any recommendations that might further reduce the risk of laminitis in these cases. Although reduced cyclic limb loading (and subsequent lamellar ischaemia) is a likely culprit, further research will be critical to identifying the underlying mechanisms and developing preventative protocols for this form of laminitis.

Treating existing laminitis: is the lesion reversible?

Even if we are able to better predict and prevent laminitis in the future, there will always be horses that escape these efforts and proceed to develop the disease. Chronic laminitis is characterised by a loss of the normal intricate architecture of the dermo-epidermal junction: the surface area of attachment, and presumably its strength, is markedly reduced [35]. Furthermore, the accumulation of dysplastic lamellar epidermal tissue results in the formation of the lamellar wedge, a gross anatomical distortion. The nature of this lesion, together with the perpetual contribution of mechanical distraction associated with weightbearing, would appear to preclude the possibility of reversion towards the original lamellar architecture and strength. New evidence in this virtual issue [36] suggests that the lamellae do retain the ability to remodel, apparently in response to mechanical stress. Lamellar epidermal remodelling and repair is indeed remarkable in response to surgical wall stripping [37], but deleteriously absent in laminitis. Weakening and destabilisation of the lamellar connection as a whole coupled with ongoing mechanical distraction may play a role; however, in a study included in this virtual issue, Carter et al. [38] have identified that laminitis tissue has a reduced potential to effectively remodel due to reduced epidermal stem cell activity. As they suggest, the transplantation of autologous epidermal stem cells has great potential as a regenerative therapy for laminitis.

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