Pathways of Prostaglandin-Mediated Recovery of Ischemia-Injured Intestine.

Abstract

Colic is a leading cause of death in horses. Many of these deaths are attributable to the effects of absorption of endotoxin through a compromised intestinal barrier and the systemic effects of endotoxemia, which are mediated by cyclooxygenase (COX) elaborated prostaglandins (PGs). Horses with colic are commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs), such as flunixin meglumine to inhibit prostanoid production but PGs are required for recovery of intestinal barrier function after ischemic-injury. Administration of non-selective COX inhibitors such as flunixin meglumine inhibit PG production and therefore recovery of intestinal barrier function in the horse after ischemic-injury. The aims of this work were firstly to evaluate the intra-cellular signaling pathways involved in this PG-mediated recovery using a porcine model of intestinal ischemia, and secondly to use an equine model of intestinal ischemia to determine if the NSAID meloxicam would permit PG-mediated recovery of intestinal barrier function after ischemic-injury. We found that a luminal osmotic gradient generated by PG-mediated chloride secretion signals via phosphatidylinositol-3-kinase (PI3K) to close the lateral intercellular space and the intercellular tight junction. Furthermore, PI3K signaling permits PG-mediated redistribution of the tight junction proteins zonula occludens-1 and occludin back to the tight junction after ischemic-injury. We found that the downstream effector of the small GTPase Rho, Rho kinase (ROCK) was also critical for PG-mediated recovery of barrier function, as was protein kinase C delta (PKC). PGs also caused upregulation of PKC expression in ischemia-injured mucosa, an effect that was partially mediated by ROCK.

We found in equine studies that the COX-2 preferential inhibitor meloxicam permitted recovery of ischemia-injured equine jejunum to a similar degree as horses not treated with NSAIDs. In contrast, flunixin retarded recovery of intestinal barrier function after ischemic-injury and caused increased flux of lipopolysaccharide in ischemia-injured jejunal mucosa, compared to horses that were not treated with flunixin. Meloxicam provided comparable analgesia and beneficial effects on clinical parameters as flunixin; meloxicam may be beneficial in treatment of colic in the horse, provided further studies are conducted.