Ischemia in equine intestine – mechanisms of injury and methods of treatment
Intestinale Ischämie beim Pferd – Pathomechanismen und Behandlungsmethoden
Freeman D E, Grosche A
DOI: 10.21836/PEMen20120402
Year: 2012
Volume: 28
Issue: 4
Pages: 366-387
The importance of reperfusion injury in equine intestine is controversial and unclear. Large colon volvulus and small intestinal strangulation are the most devastating causes of intestinal ischemia in horses and result in severe mucosal damage, barrier dysfunction, endotoxic shock and death. Although essential for tissue recovery, reperfusion after these types of ischemia could exacerbate intestinal injury. Responses to ischemia and reperfusion (I/R) involve a series of synchronized biochemical, cellular and structural changes characterized by generation of reactive oxygen metabolites, activation of immune cells, and epithelial cell degeneration and death. The intensity of neutrophil activation and influx is central to the process of reperfusion injury and the associated inflammatory events. The classic paradigm of reperfusion injury is best displayed after the segmental hypoperfusion or low-flow ischemia model, in which arterial inflow is adjusted to 20% of normal baseline flow, and then allowed to return to normal or greater values during reperfusion. In such cases, injury during the ischemic phase is mild, compared with the reperfusion injury that follows. Although there is some evidence of reperfusion injury in equine colon and jejunum after low-flow ischemia, attempts to ameliorate this by pharmacologic means have met with only moderate success. A multimodal approach, using solutions designed to improve survival in transplanted organs, seems to hold the greatest promise, although these have not been embraced in the clinical setting. Expense and difficulties in delivery are the two most serious limitations. Recent studies to assess the effect of colonic I/R on equine pelvic flexure involved a complete ischemia model that was similar to the clinical lesion, and for periods of 1 to 2 hours of ischemia followed by 30 minutes, 4 hours, or 18 hours of reperfusion. Ischemia caused degeneration and detachment of epithelial cells, early apoptosis, and opening of tight junctions (TJs), all of which decreased transepithelial resistance (TER) and increased mannitol flux when the tissues were studied in vitro. Autophagy was a prominent feature in epithelial cells after 1 hour of ischemia. Reperfusion was characterized by apoptosis, epithelial regeneration, and closure of TJs with improved TER and reduced mannitol leakage. Neutrophils infiltrated colonic mucosa during reperfusion, and macrophages, mast cells and eosinophils were activated during I/R. Equine colonic mucosa subjected to ischemia can repair rapidly and regain barrier integrity during reperfusion, despite intense mucosal inflammation. Recently, attention has focused on inflammation induced by intestinal handling and on remote organ responses to intestinal injury, both of which could be highly relevent to postoperative management of horses that undergo colic surgery. The use of lidocaine in a continuous rate infusion is a popular approach to ameliorate the intestinal inflammatory response after colic surgery, although there is no evidence that it has an antiinflammatory effect in horses. Recent studies on use of nonsteroidal antiinflammatory drugs (NSAIDs) in horses have shown that selective cyclooxygenase inhibitors, such as firocoxib, might be more supportive of repair in small intestinal mucosa after ischemic injury than less selective NSAIDs, such as flunixin meglumine (FM). Similar studies in equine colon demonstrated that FM did not affect healing and barrier recovery in this organ after ischemia, so this NSAID might affect healing in different ways in these two parts of the equine intestinal tract. However, in the jejunum, the clinical relevance of the effect of FM is unknown and its postoperative benefits might well negate any minor effect on transepithlial permeability. Despite many years of investigation, the clinical relevance of I/R in equine colic patients is unknown. Experimental design, types and durations of I/R, differences between intestinal segments and even species differences could explain the failure to repeat the findings in laboratory animal studies. Also, endpoints to measure the response to pharmacologic prevention, problems with timing and dosages of drugs, and the relative importance of different pathways and mediators in response to ischemia could explain our failures.