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

flunixin;meloxicam;tight junction;ischemic;horse;pig

Little, Dianne ; Samuel L. Jones, Committee Member,Matthew P. Gerard, Committee Member,Jody L. Gookin, Committee Member,Anthony T. Blikslager, Committee Chair,Little, Dianne ; Samuel L. Jones ; Committee Member ; Matthew P. Gerard ; Committee Member ; Jody L. Gookin ; Committee Member ; Anthony T. Blikslager ; Committee Chair

University:North Carolina State University

关键词: flunixin;    meloxicam;    tight junction;    ischemic;    horse;    pig;   

Others  :  https://repository.lib.ncsu.edu/bitstream/handle/1840.16/4623/etd.pdf?sequence=1&isAllowed=y

美国|英语

来源: null

【 摘 要 】

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.