One question that still must be answered, says James Belknap, DVM, PhD, The Ohio State University, is with all the different
kinds of laminitis, do they all follow the same pathway? In each case it looks the same as in human sepsis, what human physicians
call systemic inflammatory response. Whether it's initiated by colitis, metritis, a grain overload or a post-colon torsion
surgery, the horses usually have brick-red membranes, high heart rate and thready pulse. Virtually everything human physicians
look at is a systemic inflammatory response. What is being studied in horses is what role does the leukocyte play? What they
found in human organ failure is that sepsis is mainly due to leukocyte infiltration into the organs, expressing ROS (reactive
oxygen species — free radicals). Where they used to think it was just ischemia, they're finding now it's really not ischemia
as much as it is damage to the mitochondria, and then the cells can't function correctly. Belknap and colleagues then did
a corollary study in horses.
Using the black walnut laminitis model, a marked infiltration of leukocytes into the laminae during the developmental stage
of the disease was found.
"Interestingly, if you look at those horses at that stage, their feet are normal. They're not lame; they do not have a bounding
pulse, but they already have an incredible increase in inflammatory cytokine expression," Belknap explains. "Along with cytokines,
there is an incredible neutrophil emigration from the blood vessels into the laminae, very similar to human sepsis. What we
are finding with most of these laminitis cases, whether it's a colitis case or carbo-hydrate overload from lush grass, you're
ending up with a GI disruption and absorption of bacterial toxins, leading to systemic inflammation and leukocyte emigration
out of the blood vessels into these tissues. As black walnut toxicity has a much more rapid onset, it is likely that a toxin
from the heartwood is absorbed, which leads directly to systemic inflammation. I think it's very likely that the laminar failure
that follows is similar to what they're finding in human organ failure in sepsis. Previously, organ failure in human sepsis
was thought to be due to low blood flow, ischemia. They found otherwise. It's just that the cells can't use the oxygen because
they have such a high load of ROS and inflammatory cytokines that lead to damage to the mitochondria. In equine medicine,
we're just getting there right now."
Recently, Belknap has found that the same leukocyte infiltration occurs simultaneously in the skin, which he suggests is further
evidence that the inflammatory changes seen are not due to an isolated ischemic episode in the foot.
But some researchers do notice circulation problems in the early stages of the disease.
"Using multiple forms of laminitis, we know positively that there is a decrease in blood flow to the foot during the developmental
stage(s) before lameness," Hood says. "At the occurrence of lameness, it is increasing. Just after the occurrence of lameness,
blood flow gets abnormally high. Just because there is a decrease in blood flow during the developmental stage doesn't mean
that there is ischemia.
"In a study in horses where blood flow to the foot was occluded for a short period of time, the same lesions that you see
in clinical laminitis were created. Histologically, the same pattern is seen as blood flow is shut off and allowed to flow
to the foot again. Mild foot pain accompanied the model. This suggests that there is an ischemic change creating the lesions
that we're seeing in the laminar interface," Hood suggests. "It may be absolutely correct that it is not ischemia, as Belknap
suggests, though we don't know that yet. I'm not saying he's wrong, but that's the question until it is proven. The inflammation
may cause changes in blood flow, and changes in blood flow may cause inflammation. According to our data, you can establish
a theoretical link to ischemia. Road founder, septic shock, patients with colitis, retained placentas, carbohydrate overload,
fluid imbalance, etc., with all these divergent causes, you can show that ischemia is there."