LAMINITIS

= Inflammation of the laminae

Inflammatory Theory

The name was given to the condition because it was thought that the heat and strong pulse indicated an inflammatory process occurring in the foot and the pain was due to swelling in the confined space of the hoof.

Inflammation is certainly present in acute laminitis, seen both histologically and biochemically.

Anti-inflammatory drugs, steroids and non-steroidal anti-inflammatory (NSAIDS) drugs do not prevent laminitis, and in fact, steroids can trigger laminitis.

It is generally accepted now that this inflammation does not cause laminitis but occurs after it is triggered.

What we don‘t know is whether it is involved in the continuing progression of the condition and whether our treatment regime should involve trying to reduce inflammation.

Vascular Theory

The blood supply to the feet of horses has some peculiarities.

As well as the normal route for blood passing from the arteries to arterioles, through the capillaries back through the venules to the veins, they have connecting blood vessels between the arterioles and the venules. These are called arteriovenous anastomoses (AVA) or arteriovenous shunts.

It has been proposed that laminitis is caused by prolonged shunting of blood through these anastomoses thus bypassing the capillaries and depriving them of oxygen and other nutrients.

This would result in ischaemia, due to the lack of oxygen, causing the bond between the horny laminae of the hoof wall and the sensitive laminae overlying the pedal bone to break down.

It is proposed that this ischaemia occurs in the developmental stage of laminitis and that when the signs of acute laminitis appear the heat in the feet, the increased digital pulse and part of the pain is caused by reperfusion and oedema of the affected laminae.

(The other peculiarity is that there are very few valves in the veins of the horse‘s foot.)

Enzymatic Theory

It has been demonstrated that the primary lesion of laminitis is the degradation of the basement membrane (BM), the connective tissue bond between the hoof and the pedal bone.

There are enzymes, Matrix Metalloproteinase 2 & 9 (MMP-2, MMP-9) that are present in the feet, in the basal cells of the secondary epidermal lamellae.

They are thought to be involved in the normal growing process, allowing the movement of the hoof wall to pass over the fixed structure of the pedal bone. They are stored in an inactive form and are activated and inhibited in an extremely controlled manner so that the support and stability of the pedal bone is maintained.

MMPs act on the attachments of the basal cells to the BM as well as the BM itself.

In the developmental stage of laminitis, it appears that MMPs are activated in an uncontrolled manner causing disintegration of the BM and its attachments.

The theory is that a "trigger factor", released from the caecum/large intestine, reaches the foot in the blood and activates the MMPs.

Clinical laminitis will occur if the destruction of the BM is to a level that there is loss of support of the pedal bone.

It is generally accepted that this is the process that occurs in the "carbohydrate overload" induced laminitis.

Although the basement membrane is the site of separation in all forms of laminitis, it has not been explained how this mechanism could be involved in laminitis from other causes.

Glucose Theory

It has been shown that when glucose is removed from the culture medium of explant experiments that a dermal/epidermal separation, similar to that produced by MMP activation, occurs.

This led to the theory that a form of laminitis occurred in horses that had problems that affected glucose uptake in the tissues of the feet.

This theory was put forward as an explanation for laminitis occurring in conditions that would induce a metabolic shift away from glucose consumption - in septicaemia, corticosteroid therapy, Equine Cushing‘s Disease and Metabolic Syndrome.

In explant experiments, it has been demonstrated that both glucose deprivation and MMP activation cause separation at the dermo-epidermal junction but by breaking down different supporting bonds.

However, the hemidesmosomes that disappear with glucose deprivation in vitro are also lost following fructans induced laminitis in horses.

So I believe that the Enzymatic and Glucose Theories can both be involved in the development of laminitis and that the inflammation and vascular disruption that occurs is a consequence rather than a cause of the condition.

A lot of research has been done into the changes that occur in the foot in an episode of laminitis, but it is hard to know which physical properties or chemical reactions are relevant in the process.

Which factors are involved in the development and which occur subsequently?

Even though some factors may not be involved in the development of laminitis, are they relevant in continuing the process?

How many mechanisms are there that trigger laminitis?

My doubts about this theory

A lot of the work showing impairment of the blood flow was done studying horses showing the signs of acute laminitis and not during the developmental stage. (17)

Although it has been show that many factors can affect the blood vessels, and thus the blood flow, in horses‘ feet, none have been demonstrated to trigger laminitis. (18)

Investigations, using black walnut extract to trigger laminitis, found little indication of hypoxia/ischaemia in the lamellar tissue in either the developmental or the clinical phase. (1)

It seems that the AVA are part of the thermo-regulatory mechanism of the horse‘s foot and that, when standing in ice and snow, both the AVA and the capillaries will open in order to maintain the hoof temperature, to avoid freezing.

(Ducks apparently have AVAs present in their feet, presumably for the same reason.)

It has been demonstrated that laminitis occurs in horses that have prolonged period of vasodilation during the developmental stage of laminitis. (5)

Maintaining the feet of horses in ice slurry has been shown to be effective in preventing clinical laminitis. (9) (13) (16)

I would suggest that when laminitis is developing, with the disintegration of the basement membrane and loss of support for the pedal bone, the distortion of the secondary epidermal lamellae (laminae) will stretch the capillaries and with thus decrease blood flow through them.

Impaired blood flow will occur in laminitis but as a result rather than the cause of the developmental stage.

Dr Pollitt and his co-workers in Queensland University have spent the past fifteen years, firstly investigating the processes that occur in the normal foot and subsequently the changes that occur in the foot during an episode of laminitis.

This methodical investigation produced the theory that there is enzymatic degradation of the basement membrane occurring in the developmental stage of laminitis following carbohydrate overload.

• Identified the basement membrane (BM) with histological staining and showed that this was the site of separation. (2)
• Was able to correlate BM disruption with degree of lameness. (2) (3)
• Proposal that MMP activated by a blood borne trigger factor, investigated by using lamellar explants (hoof lamellar tissue cultured in culture medium).
• Explants caused to separate if the MMP activator (APMA) added to the medium but failed to do so if APMA and an MMP inhibitor both added. (4)
• Demonstrated that laminitis occurs in horses that have prolonged period of vasodilation during the developmental stage of laminitis. (5)
• Streptococci bacteria in the caecum seemed a likely source, since in the presence of virginiamycin horses were protected from carbohydrate induced laminitis and Streptococci were absent from the hindgut.
• Explant experiments indicated that bacterial broth cultures and purified bacterial proteases stimulated MMP activation and were inhibited by a MMP inhibitor. (8)
• Four Gram-positive Streprococcus species and three Gram-negative bacteria shown to induce a dose-dependant activation of MMPs in explants.
• Explant experiments indicated that lamellar epidermal basal cells were sensitive to fluctuations of glucose concentration. (6)
• Started to experiment with a commercially produced fructan following the identification of a correlation between the occurrence of laminitis and the feeding of certain grass species which could store fructans in high concentrations.
• All horses given doses of this fructan developed laminitis in at least one foot and was more severe in those given higher doses. (11)
• By placing one leg in a boot containing ice slurry for 48hr, showed that horses tolerated cryotherapy well without adverse reaction or lameness. (9)
• Induced laminitis in 6 horses which had one foot in a boot containing ice slurry. Lameness and foot lifting were not seen in the cooled limb and histological changes and expression of MMP-2 mRNA were significantly less than in the untreated feet. (13)
• Separation at the dermo-epidermal junction, when tension is applied to explants, occurs when they are cultured without glucose or with a MMP activator.
However it was shown that the separation was not exactly the same. (14)

The lack of glucose reduced the bonds between the epidermal basal cells but did not affect the filaments connecting the basal cells to the BM. Activation of the MMPs caused the basal cell/BM anchoring filaments to disappear but did not affect the epidermal basal cell bonds.