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OBJECTIVE To determine the degree of histomorphometric damage in dorsal colon and pelvic flexure biopsy specimens (DCBSs and PFBSs, respectively) obtained from horses with large colon volvulus (LCV) and assess the accuracy of predicting short-term outcome for those horses on the basis of DCBS or PFBS characteristics. ANIMALS 18 horses with ≥ 360° LCV that underwent large colon resection. PROCEDURES During surgery, biopsy specimens from the dorsal colon resection site and the pelvic flexure (when available) were collected from each horse. Interstitial-to-crypt (I:C) ratio (ratio of the lamina propria space occupied by the interstitium to that occupied by crypts), hemorrhage within the lamina propria (mucosal hemorrhage score [MHS] from 0 to 4), and percentage losses of glandular and luminal epithelium were determined in paired biopsy specimens and compared to determine optimal cutoff values for calculating the accuracy of DCBS and PFBS characteristics to predict short-term outcome (survival or nonsurvival after recovery from surgery). RESULTS Paired biopsy specimens were obtained from 17 of the 18 horses. The I:C ratio and percentage glandular epithelial loss differed between DCBSs and PFBSs. For DCBSs, an I:C ratio ≥ 0.9 and MHS ≥ 3 each predicted patient nonsurvival with 77.8% accuracy. For PFBSs, an I:C ratio ≥ I and MHS ≥ 3 predicted patient nonsurvival with 70.6% and 82.4% accuracy, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Although different, histomorphometric measurements for either DCBSs or PFBSs could be used to accurately predict short-term outcome for horses with LCV that underwent large colon resection, and arguably PFBSs are easier to collect.

Simple Summary Equine colic places a substantial financial burden on horse owners and the equine industry each year. Equine veterinary research is focused on preventing colic on the farm whenever possible and improving treatment options available to veterinarians in the field and referral hospitals. It is important for scientists to have a detailed understanding of the intestinal damage created by different types of colic in foals and adult horses so they can better target certain cell types or tissue systems when investigating new treatment options. This review article summarizes recent works in the field of intestinal injury research and describes the potential roles of various intestinal systems, such as the enteric nervous system (ENS), in repairing the intestine after colic injury and how these systems mature in early life. Abstract Colic is a leading cause of death in horses, with the most fatal form being strangulating obstruction which directly damages the intestinal barrier. Following surgical intervention, it is imperative that the intestinal barrier rapidly repairs to prevent translocation of gut bacteria and their products and ensure survival of the patient. Age-related disparities in survival have been noted in many species, including horses, humans, and pigs, with younger patients suffering poorer clinical outcomes. Maintenance and repair of the intestinal barrier is regulated by a complex mucosal microenvironment, of which the ENS, and particularly a developing network of subepithelial enteric glial cells, may be of particular importance in neonates with colic. Postnatal development of an immature enteric glial cell network is thought to be driven by the microbial colonization of the gut and therefore modulated by diet-influenced changes in bacterial populations early in life. Here, we review the current understanding of the roles of the gut microbiome, nutrition, stress, and the ENS in maturation of intestinal repair mechanisms after foaling and how this may influence age-dependent outcomes in equine colic cases.

Postoperative ileus (POI), a decrease in gastrointestinal motility after surgery, is an important problem facing human and veterinary patients. Retrospective study indicates that 37.5% of horses that develop POI following small intestinal resection will not survive to discharge. The two major components of POI pathophysiology are a neurogenic phase which is then propagated by an inflammatory phase. Perioperative care has also been implicated, namely the use of opioid therapy, inappropriate fluid therapy and electrolyte imbalances. Current therapy for POI variably includes an early return to feeding to induce physiological gastrointestinal motility, reducing the inflammatory response with agents such as non-steroidal anti-inflammatory drugs, and use of prokinetic therapy such as lidocaine. However, optimal management of POI remains controversial. A better understanding of the roles of the gastrointestinal microbiota, intestinal mucosal barrier function, the post-surgical inflammatory response, as well as enteric glial cells, a component of the enteric nervous system, in modulating postoperative motility and the pathogenesis of POI may provide future targets for prevention and/or therapy of POI.

Management factors associated with colic, particularly related to stall confinement and nutrition, have been linked to alterations in gastrointestinal mucosal transport, motility, and microbiome, which in turn creates conditions that induce colic. In particular, meal feeding creates large changes in water movement in and out of the colon and alters the microbiome. These conditions may in turn result in colic conditions such as large colon impaction or large colon volvulus. In addition, a range of management and nutritional factors have been found to place horses at risk of select colic conditions such as ileal impaction. Other specific colic conditions, such as strangulating lipomas, may be related to fat metabolism in geldings and ponies, although the association with nutrition and the endocrine system are less well defined. It has long been understood that parasites are associated with colic, and with the advent of highly effective anthelmintics, parasite-induced colic has been markedly reduced. Nonetheless, equine mangers and veterinarians have to be aware of changes in parasite resistance or patterns of activity, such as the resurgence of large strongyles with surveillance-based management of parasites. Overall, understanding management risk factors can lead to recommendations that prevent colic in horses. Additional study of these factors may ultimately lead to reductions in the prevalence of colic by suggesting optimal management practices.

Background Equine coronavirus (ECoV) is an emerging pathogen associated with fever and enteric disease in adult horses. Clinical features of ECoV infection have been described, but no study has compared these features to those of Salmonella infections. Objectives Compare the clinical features of ECoV infection with enteric salmonellosis and establish a disease signature to increase clinical suspicion of ECoV infection in adult horses. Animals Forty-three horses >1 year of age with results of CBC, serum biochemistry, and fecal diagnostic testing for ECoV and Salmonella spp. Methods Medical records of horses presented to the North Carolina State University Equine and Farm Animal Veterinary Center (2003-016) were retrospectively reviewed. Horses were divided into 3 groups based on fecal diagnostic test results: ECoV-positive, Salmonella-positive, or unknown diagnosis (UNK). Time of year presented, clinical signs, CBC, and serum biochemistry test results were recorded. Data were analyzed by 1-way analysis of variance, Kruskal-Wallis test, or Fisher's exact test with significance set at P Results Most common presenting complaints were fever and colic and were similar across groups. Horses with ECoV had significantly decreased neutrophil counts when compared to those with no diagnosis but were not different from horses with Salmonella. Horses with Salmonella had significantly lower mean leukocyte counts compared to those with UNK. No significant differences were found among groups for any other examined variable. Conclusions and clinical importance Equine coronavirus and Salmonella infections share clinical features, suggesting both diseases should be differential diagnoses for horses with fever and enteric clinical signs.

Disruptions in the intestinal epithelial barrier can result in devastating consequences and a multitude of disease syndromes, particularly among preterm neonates. The association between barrier dysfunction and intestinal dysbiosis suggests that the intestinal barrier function is interactive with specific gut commensals and pathogenic microbes. In vitro and in vivo studies demonstrate that probiotic supplementation promotes significant upregulation and relocalization of interepithelial tight junction proteins, which form the microscopic scaffolds of the intestinal barrier. Probiotics facilitate some of these effects through the ligand-mediated stimulation of several toll-like receptors that are expressed by the intestinal epithelium. In particular, bacterial-mediated stimulation of toll-like receptor-2 modulates the expression and localization of specific protein constituents of intestinal tight junctions. Given that ingested prebiotics are robust modulators of the intestinal microbiota, prebiotic supplementation has been similarly investigated as a potential, indirect mechanism of barrier preservation. Emerging evidence suggests that prebiotics may additionally exert a direct effect on intestinal barrier function through mechanisms independent of the gut microbiota. In this review, we summarize current views on the effects of pro- and prebiotics on the intestinal epithelial barrier as well as on non-epithelial cell barrier constituents, such as the enteric glial cell network. Through continued investigation of these bioactive compounds, we can maximize their therapeutic potential for preventing and treating gastrointestinal diseases associated with impaired intestinal barrier function and dysbiosis.

Eosinophilic esophagitis (EoE) is a chronic atopic disease that has become increasingly prevalent over the past 20 years. A first-line pharmacologic option is topical/swallowed corticosteroids, but these are adapted from asthma preparations such as fluticasone from an inhaler and yield suboptimal response rates. There are no FDA-approved medications for the treatment of EoE, and esophageal-specific drug formulations are lacking. We report the development of two novel esophageal-specific drug delivery platforms. The first is a fluticasone-eluting string that could be swallowed similar to the string test “entero-test” and used for overnight treatment, allowing for a rapid release along the entire length of esophagus. In vitro drug release studies showed a target release of 1 mg/day of fluticasone. In vivo pharmacokinetic studies were carried out after deploying the string in a porcine model, and our results showed a high local level of fluticasone in esophageal tissue persisting over 1 and 3 days, and a minimal systemic absorption in plasma. The second device is a fluticasone-eluting 3D printed ring for local and sustained release of fluticasone in the esophagus. We designed and fabricated biocompatible fluticasone-loaded rings using a top-down, Digital Light Processing (DLP) Gizmo 3D printer. We explored various strategies of drug loading into 3D printed rings, involving incorporation of drug during the print process (pre-loading) or after printing (post-loading). In vitro drug release studies of fluticasone-loaded rings (pre and post-loaded) showed that fluticasone elutes at a constant rate over a period of one month. Ex vivo pharmacokinetic studies in the porcine model also showed high tissue levels of fluticasone and both rings and strings were successfully deployed into the porcine esophagus in vivo. Given these preliminary proof-of-concept data, these devices now merit study in animal models of disease and ultimately subsequent translation to testing in humans.

Intestinal ischemia results in mucosal injury, including paracellular barrier loss due to disruption of tight junctions. Larazotide acetate (LA), a small peptide studied in Phase III clinical trials for treatment of celiac disease, regulates tight junctions (TJs). We hypothesized that LA would dose-dependently hasten recovery of intestinal ischemic injury via modulation of TJs. Ischemia-injured tissue from 6-8-week-old pigs was recovered in Ussing chambers for 240-minutes in the presence of LA. LA (1 μM but not 0.1 μM or 10 μM) significantly enhanced transepithelial electrical resistance (TER) above ischemic injured controls and significantly reduced serosal-to-mucosal flux LPS (P.05). LA (1 μM) enhanced localization of the sealing tight junction protein claudin-4 in repairing epithelium. To assess for the possibility of fragmentation of LA, anin vitroenzyme degradation assay using the brush border enzyme aminopeptidase M, revealed generation of peptide fragments. Western blot analysis of total protein isolated from uninjured and ischemia-injured porcine intestine showed aminopeptidase M enzyme presence in both tissue types, and mass spectrometry analysis of samples collected duringex vivoanalysis confirmed formation of LA fragments. Treatment of tissues with LA fragments had no effect alone, but treatment with a fragment missing both amino-terminus glycines inhibited barrier recovery stimulated by 1 μM LA. To reduce potential LA inhibition by fragments, a D-amino acid analog of larazotide Analog #6, resulted in a significant recovery response at a 10-fold lower dose (0.1 μM) similar in magnitude to that of 1 μM LA. We conclude that LA stimulates repair of ischemic-injured epithelium at the level of the tight junctions, at an optimal dose of 1 μM LA. Higher doses were less effective because of inhibition by LA fragments, which could be subverted by chirally-modifying the molecule, or microdosing LA.

There is no FDA approved therapy for the treatment of celiac disease (CeD), aside from avoidance of dietary gluten. Larazotide acetate (LA) is a first in class oral peptide developed as a tight junction regulator, which is a lead candidate for management of CeD. A delayed release formulation was tested in vitro and predicted release in the mid duodenum and jejunum, the target site of CeD. The aim of this study was to follow the concentration versus time profile of orally administered LA in the small intestine using a porcine model. A sensitive liquid chromatography/tandem mass spectrometry method was developed to quantify LA concentrations in porcine intestinal fluid samples. Oral dosing of LA (1 mg total) in overnight fasted pigs resulted in time dependent appearance of LA in the distal duodenum and proximal jejunum. Peak LA concentrations (0.32–1.76 μM) occurred at 1 hour in the duodenum and in proximal jejunum following oral dosing, with the continued presence of LA (0.02–0.47 μM) in the distal duodenum and in proximal jejunum (0.00–0.43 μM) from 2 to 4 hours following oral dosing. The data shows that LA is available in detectable concentrations at the site of CeD.

The pig is a powerful model for intestinal barrier studies, and it is important to carefully plan animal care and handling for optimal study design as psychological and physiological stressors significantly impact intestinal mucosal barrier function. Here, we report the effects of a period of environmental acclimation versus acute transport stress on mucosal barrier repair after intestinal ischemic injury. Jejunal ischemia was induced in young pigs which had been allowed to acclimate to a biomedical research housing environment or had been transported immediately prior to experimental injury (non-acclimated). Mucosa was then incubated ex vivo on Ussing chambers. In uninjured mucosa, there was no difference in transepithelial electrical resistance (TEER) or epithelial integrity between groups. However, acclimated pigs had increased macromolecular flux as compared to non-acclimated pigs during the first hour of ex vivo incubation. Ischemia induced greater epithelial loss in non-acclimated pigs as compared to acclimated pigs, yet this group achieved greater wound healing during recovery. Non-acclimated pigs had more robust TEER recovery ex vivo following injury versus acclimated pigs. The expression pattern of the tight junction protein claudin-4 was disrupted in acclimated pigs following recovery but showed enhanced localization to the apical membrane in non-acclimated pigs following recovery. Acute transport stress increases mucosal susceptibility to epithelial loss but also primes the tissue for a more robust barrier repair response. Alternatively, environmental acclimation increases leak pathway and diminishes barrier repair responses after ischemic injury.

Esophageal injury from acid exposure related to gastroesophageal reflux disease is a common problem and a risk factor for development of Barrett’s esophagus and esophageal adenocarcinoma. Our previous work highlights the benefits of using porcine esophagus to study human esophageal disease because of the similarities between porcine and human esophagus. In particular, esophageal submucosal glands (ESMGs) are present in human esophagus and proximal porcine esophagus but not in rodent esophagus. Although CFTR is expressed in the ducts of ESMGs, very little is known about CFTR and alternate anion channels, including ClC-2, in the setting of acid-related esophageal injury. After finding evidence of CFTR and ClC-2 in the basal layers of the squamous epithelium, and in the ducts of the ESMGs, we developed an ex vivo porcine model of esophageal acid injury. In this model, esophageal tissue was placed in Ussing chambers to determine the effect of pretreatment with the ClC-2 agonist lubiprostone on tissue damage related to acid exposure. Pretreatment with lubiprostone significantly reduced the level of acid injury and significantly augmented the recovery of the injured tissue ( P < 0.05). Evaluation of the interepithelial tight junctions showed well-defined membrane localization of occludin in lubiprostone-treated injured tissues. Pretreatment of tissues with the Na+-K+-2Cl−cotransporter inhibitor bumetanide blocked lubiprostone-induced increases in short-circuit current and inhibited the reparative effect of lubiprostone. Furthermore, inhibition of ClC-2 with ZnCl2blocked the effects of lubiprostone. We conclude that ClC-2 contributes to esophageal protection from acid exposure, potentially offering a new therapeutic target.NEW & NOTEWORTHY This research is the first to describe the presence of anion channels ClC-2 and CFTR localized to the basal epithelia of porcine esophageal mucosa and the esophageal submucosal glands. In the setting of ex vivo acid exposure, the ClC-2 agonist lubiprostone reduced acid-related injury and enhanced recovery of the epithelial barrier. This work may ultimately provide an alternate mechanism for treating gastroesophageal reflux disease.

The intestinal epithelial monolayer forms a transcellular and paracellular barrier that separates luminal contents from the interstitium. The paracellular barrier consists of a highly organized complex of intercellular junctions that is primarily regulated by apical tight junction proteins and tight junction-associated proteins. This homeostatic barrier can be lost through a multitude of injurious events that cause the disruption of the tight junction complex. Acute repair after injury leading to the reestablishment of the tight junction barrier is crucial for the return of both barrier function as well as other cellular functions, including water regulation and nutrient absorption. This review provides an overview of the tight junction complex components and how they link to other plasmalemmal proteins, such as ion channels and transporters, to induce tight junction closure during repair of acute injury. Understanding the components of interepithelial tight junctions and the mechanisms of tight junction regulation after injury is crucial for developing future therapeutic targets for patients experiencing dysregulated intestinal permeability.

BACKGROUND Continuous digital cryotherapy experimentally prevents development and reduces severity of sepsis-associated laminitis. A sleeve style ice boot where ice is in direct contact with the skin, and water drains from the boot is being used clinically for distal limb cryotherapy. The degree of cooling achieved by this boot is unknown. OBJECTIVES Evaluate skin and lamellar cooling after application of the ice sleeve in healthy horses, and the same horses during an endotoxaemia model. STUDY DESIGN Prospective study, crossover design. METHODS In eight healthy horses thermocouples were inserted into dorsal lamellae of both front feet, and under skin on both metacarpi. One forelimb received cryotherapy using sleeve style ice boot, with contralateral limb as control. Temperature was recorded on data logging devices at 5 min intervals during each cryotherapy session. Day 1: temperature data was collected for healthy horses. Day 2: data was collected for the same horses during i.v. administration of endotoxin. RESULTS In healthy and endotoxaemic horses, the sleeve style ice boot significantly decreased mean skin (7.2°C and 5.8°C respectively) and lamellar (10.8°C and 9.6°C respectively) temperatures compared with control limbs (P

Background Sucralfate is a gastroprotectant with no known systemic effects. The efficacy of sucralfate for prevention and treatment of stress‐related mucosal diseases (SRMD) in dogs is unknown. Hypothesis/Objectives To develop a canine ex vivo model of SRMD and to determine the effect of sucralfate on mucosal barrier function in this model. Animals Gastric antral mucosa was collected immediately postmortem from 29 random‐source apparently healthy dogs euthanized at a local animal control facility. Methods Randomized experimental trial. Sucralfate (100 mg/mL) was applied to ex vivo canine gastric mucosa concurrent with and after acid injury. Barrier function was assessed by measurement of transepithelial electrical resistance (TER) and radiolabeled mannitol flux. Results Application of acidified Ringers solution to the mucosal side of gastric antrum caused a reduction in gastric barrier function, and washout of acidified Ringers solution allowed recovery of barrier function (TER: 34.0 ± 2.8% of control at maximum injury, 71.3 ± 5.5% at recovery, P

The equine intestinal mucosa is intimately involved in maintaining homeostasis both on a systemic level by controlling extracellular fluid movement and at the local level to maintain barrier function. Horses are particularly susceptible to the clinical syndrome of colic, with the most severe cases involving strangulating obstruction that induces ischemia. Because of the mucosal vascular architecture, the mucosal epithelium is particularly susceptible to ischemic injury. The potential for reperfusion injury has been investigated and found to play a minimal role. However, inflammation does affect mucosal repair. Mechanisms of repair, including villus contraction, epithelial restitution, and tight junction closure, are critical to reforming the mucosal barrier. Nonsteroidal anti-inflammatory drugs have an impact on this repair, particularly at the level of the tight junctions. Completion of mucosal regeneration requires proliferation, which is now being actively studied in equine enteroids. All of these aspects of equine mucosal pathobiology are reviewed in depth.

Background & Aims Although cells comprising esophageal submucosal glands (ESMGs) represent a potential progenitor cell niche, new models are needed to understand their capacity to proliferate and differentiate. By histologic appearance, ESMGs have been associated with both overlying normal squamous epithelium and columnar epithelium. Our aim was to assess ESMG proliferation and differentiation in a 3-dimensional culture model. Methods We evaluated proliferation in human ESMGs from normal and diseased tissue by proliferating cell nuclear antigen immunohistochemistry. Next, we compared 5-ethynyl-2′-deoxyuridine labeling in porcine ESMGs in vivo before and after esophageal injury with a novel in vitro porcine organoid ESMG model. Microarray analysis of ESMGs in culture was compared with squamous epithelium and fresh ESMGs. Results Marked proliferation was observed in human ESMGs of diseased tissue. This activated ESMG state was recapitulated after esophageal injury in an in vivo porcine model, ESMGs assumed a ductal appearance with increased proliferation compared with control. Isolated and cultured porcine ESMGs produced buds with actively cycling cells and passaged to form epidermal growth factor–dependent spheroids. These spheroids were highly proliferative and were passaged multiple times. Two phenotypes of spheroids were identified: solid squamous (P63+) and hollow/ductal (cytokeratin 7+). Microarray analysis showed spheroids to be distinct from parent ESMGs and enriched for columnar transcripts. Conclusions Our results suggest that the activated ESMG state, seen in both human disease and our porcine model, may provide a source of cells to repopulate damaged epithelium in a normal manner (squamous) or abnormally (columnar epithelium). This culture model will allow the evaluation of factors that drive ESMGs in the regeneration of injured epithelium. The raw microarray data have been uploaded to the National Center for Biotechnology Information Gene Expression Omnibus (accession number: GSE100543)., Graphical abstract

OBJECTIVES/GOALS: An age-dependent restitution defect in our neonatal pig intestinal ischemia model is rescued by unknown factors within homogenized mucosa of weaned pigs. A postnatally maturing network of enteric glia regulates the epithelial barrier, so we aim to show rescue is due to replacement of glial factors. METHODS/STUDY POPULATION: Jejunal tissues from suckling or weaned pigs were assessed by RNAseq and processed for immunofluorescent histology and 3-D volume imaging. Jejunal ischemia was surgically induced in weaned pigs and injured mucosa was recovered ex vivo with or without the glial inhibitor fluoroacetate (FA) while monitoring transepithelial electrical resistance (TER). RESULTS/ANTICIPATED RESULTS: Ingenuity Pathways Analysis of RNAseq data revealed significant suppression of numerous pathways critical for epithelial wound healing in suckling pigs (Z-score in vitro to further define postnatal development of barrier repair.

Intestinal ischemia is an abdominal emergency with a mortality rate >50%, leading to epithelial barrier loss and subsequent sepsis. Epithelial renewal and repair after injury depend on intestinal epithelial stem cells (ISC) that reside within the crypts of Lieberkühn. Two ISC populations critical to epithelial repair have been described: 1) active ISC (aISC; highly proliferative; leucine-rich-repeat-containing G protein-coupled receptor 5 positive, sex determining region Y-box 9 positive) and 2) reserve ISC [rISC; less proliferative; homeodomain only protein X (Hopx)+]. Yorkshire crossbred pigs (8–10 wk old) were subjected to 1–4 h of ischemia and 1 h of reperfusion or recovery by reversible mesenteric vascular occlusion. This study was designed to evaluate whether ISC-expressing biomarkers of aISCs or rISCs show differential resistance to ischemic injury and different contributions to the subsequent repair and regenerative responses. Our data demonstrate that, following 3–4 h ischemic injury, aISC undergo apoptosis, whereas rISC are preserved. Furthermore, these rISC are retained ex vivo in spheroids in which cell populations are enriched in the rISC biomarker Hopx. These cells appear to go on to provide a proliferative pool of cells during the recovery period. Taken together, these data indicate that Hopx+ cells are resistant to injury and are the likely source of epithelial renewal following prolonged ischemic injury. It is therefore possible that targeting reserve stem cells will lead to new therapies for patients with severe intestinal injury. NEW & NOTEWORTHY The population of reserve less-proliferative intestinal epithelial stem cells appears resistant to injury despite severe epithelial cell loss, including that of the active stem cell population, which results from prolonged mesenteric ischemia. These cells can change to an activated state and are likely indispensable to regenerative processes. Reserve stem cell targeted therapies may improve treatment and outcome of patients with ischemic disease.

Intestinal injury, although typically associated with ischemic lesions, occurs during any obstructive intestinal disease to varying degrees depending on the type of obstruction and the extent of vascular compromise. In addition, in some instances, the intestinal lumen is patent, but there is vascular compromise—for example, in nonstrangulating infarctions. Intestinal obstructive lesions are classified as either simple or strangulating obstructions. A great deal of work has been done to assess the level of injury encountered with these lesions at surgery and during the postsurgical phase following correction and subsequent reperfusion of these lesions. Although more is known about mucosal injury than about injury encountered in other intestinal layers, it is clear that substantial injury also occurs at the levels of the serosa and the muscularis, which very likely contributes to postoperative complications such as adhesion formation and ileus. Understanding the pathophysiology of these lesions allows the surgeon to more adequately perform surgical and postoperative procedures to optimize patient survival. For example, attention has been focused on the development of intestinal injury during reperfusion, and the possibility of inhibiting these lesions with various treatments. Furthermore, to combat the postoperative complication of serosal inflammation and secondary adhesion formation, surgeons have adopted a number of new treatments.

Gastrointestinal disease is a prevalent cause of morbidity and mortality and the use of animal models have been instrumental in studying mechanisms of digestive pathophysiology. As investigators attempt to translate the wealth of basic science information developed from rodent models, large animal models provide a number of translational advantages. The pig, in particular, is arguably one of the most powerful models of human organ systems, including the gastrointestinal tract. The pig has provided important tools and insight into intestinal ischemia/reperfusion injury, intestinal mucosal repair, as well as new insights into esophageal injury and repair. Porcine model development has taken advantage of the size of the animal, allowing increased surgical and endoscopic access. In addition, cellular tools such as the intestinal porcine epithelial cell (IPEC-J2) line and porcine enteroids are providing the methodology to translate basic science findings using in-depth mechanistic analyses. Further opportunities in porcine digestive disease modeling include developing additional transgenic pig strains. Collectively, porcine models hold great promise for the future of clinically relevant digestive disease research. Keywords: Pig, Ischemia/Reperfusion Injury, Mucosal Repair, Tight Junction

REASONS FOR PERFORMING STUDY The large size of the adult horse prevents the use of advanced imaging modalities in most areas of the axial skeleton, including the lumbosacral vertebral column. Traditional imaging techniques are frequently unable to pinpoint the underlying pathology in horses with caudal back pain. In man, lumbosacral epiduroscopy is used to diagnose and treat subjects with chronic back and leg pain. This technique may close the diagnostic gap in horses with similar clinical signs. OBJECTIVES To evaluate the safety and feasibility of lumbosacral epiduroscopy in the standing adult horse. STUDY DESIGN Descriptive, experimental study. METHODS Seven adult horses weighing 504-578 kg were sedated and restrained in stocks in preparation for aseptic surgery. Vascular dilators of increasing size were inserted cranial to the first moveable vertebra caudal to the sacrum to facilitate a minimally invasive approach into the epidural space. A flexible video-endoscope was introduced and advanced as far as its 60-cm working length permitted. Pre-, intra- and post-operative plasma cortisol samples were collected, and neurological and lameness examinations were performed prior to and during the 2 weeks following the procedure. Post-mortem examinations were conducted in 5 of the 7 horses. RESULTS Standing lumbosacral epiduroscopy was well tolerated by all horses. The anatomic structures in the epidural space (dura mater, spinal nerve roots, fat and blood vessels) were followed as far cranial as the thoracolumbar region. No complications related to the procedure were noted in the 2-week monitoring period following epiduroscopy. Small, organised haematomas were identified in the sacral epidural space during necropsy in one horse. No abnormalities were seen in the other 4 animals. CONCLUSIONS Lumbosacral epiduroscopy can be performed safely in sedated standing horses. The procedure may become a valuable diagnostic tool in horses with caudal back or hindlimb pain of unknown origin.

REASONS FOR PERFORMING STUDY Clinically useful biomarkers are needed for early identification of endotoxaemic horses. Soluble CD14 (sCD14) is amplified early in response to inflammatory signals, including bacterial lipopolysaccharide (LPS), and may prove a useful biomarker for clinical endotoxaemia. OBJECTIVES The aim of this study was to determine if sCD14 could serve as a more reliable biomarker of the clinical signs of endotoxaemia, compared to measuring LPS alone. STUDY DESIGN Prospective observational study in horses at a veterinary teaching hospital. METHODS Plasma samples were collected from 20 healthy horses and 35 horses presenting for emergency evaluation. Horses were classified as clinically endotoxaemic, using previously established criteria, if they had a heart rate >70 beats/min, packed cell volume >45% and/or a lesion likely to result in endotoxaemia. Soluble CD14 was measured using a cytometric bead-based assay and LPS was measured using a Limulus amoebocyte lysate (LAL) assay. RESULTS Soluble CD14 was higher in horses classified as clinically endotoxaemic (median 1102 ng/ml, interquartile range 439 ng/ml), compared to clinically nonendotoxaemic (median 692 ng/ml, interquartile range 455 ng/ml, P = 0.03. There was no difference in LPS concentrations between clinically nonendotoxaemic (median 5.4 endotoxin units [EU]/ml, interquartile range 5 EU/ml) and endotoxaemic horses (median 7.2 EU/ml, interquartile range 17 EU/ml, P = 0.2). There was no correlation between sCD14 and LPS values in paired serum samples. LPS and sCD14 values were used to generate a receiver operating characteristic curve. The area under the curve for LPS and sCD14 was

BACKGROUND Esophagitis with eosinophilia, inflammation, and fibrosis represent a chronic condition in humans with food allergies. OBJECTIVE In this investigation, we asked whether esophagitis with an eosinophilic component is observed in young pigs rendered allergic to hen egg white protein (HEWP). METHODS Food allergy was induced in young pigs using two protocols. In one protocol, sensitized pigs were challenged by gavage with a single dose of HEWP. Clinical signs were monitored for 24 hours, and then, gastrointestinal (GI) tissues were collected for histological examination. The phenotype of circulating, ovalbumin (OVA)-specific T cells also was examined in HEWP challenged animals. In the second protocol, sensitized animals were fed HEWP for 28 days. Animals were then examined by endoscopy and gastrointestinal tissues collected for histological examination. RESULTS In pigs challenged by gavage with HEWP, clinical signs were noted in 5/6 pigs including diarrhoea, emesis, and skin rash. Clinical signs were not seen in any control group. Histological analysis revealed significant levels of oesophageal eosinophilic infiltration (P

African rhinoceros are poached for their horns using indiscriminate and aggressive methods. Rhinoceros that survive these attacks often have severe facial trauma, and treatment is limited by a lack of understanding and published information of the normal anatomy. This study was performed to investigate and describe the anatomy of the most commonly injured area of the head of the white rhinoceros (Ceratotherium simum). Two white rhinoceros cadaver heads were imaged by computed tomography and grossly dissected. A combined dorsal conchal sinus and nasal sinus (named the nasoconchal sinus) was identified and confirmed to be readily exposed by horn removal. The nasoconchal sinus communicates via a relatively large opening with the middle nasal meatus of the nasal cavity. Awareness of the combined sinus space and its single communicating pathway will assist with accurate assessment and treatment of trauma to the dorsal facial region of the white rhinoceros.

BACKGROUND: Small intestinal strangulating obstruction (SISO) is associated with endotoxaemia which leads to an increased risk of death. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat signs of endotoxaemia by inhibiting cyclo-oxygenases (COX). COX-1 is expressed constitutively and promotes gut barrier function, whereas COX-2 is inducible and contributes to the signs of endotoxaemia. In preclinical SISO trials, intestinal barrier recovery was more complete with reductions in endotoxin permeability in horses treated with COX-2 selective NSAIDs as compared with horses treated with flunixin meglumine. OBJECTIVES: We hypothesised that treatment of post-surgical SISO horses with firocoxib (COX-2 selective) would reduce the signs of endotoxaemia to a greater extent than flunixin meglumine (nonselective COX inhibitor) while continuing to provide similar levels of pain control. STUDY DESIGN: Blinded randomised clinical trial. METHODS: In addition to clinical monitoring, preoperative and 12-, 24- and 48-h post-operative plasma samples were assessed for prostaglandin E(2) (PGE(2)), thromboxane B(2) (TXB(2)), TNFα and soluble CD14 (sCD14). RESULTS: In 56 recruited SISO horses, either flunixin meglumine (1.1 mg/kg, i.v., q12h) or firocoxib (0.3 mg/kg, i.v. loading dose; 0.1 mg/kg, i.v., q24h) was given in the post-operative period in three university hospitals from 2015 to 2017. COX-2 selectivity was confirmed by a relative lack of inhibition of the COX-1 prostanoid TXB(2) by firocoxib and significant inhibition by flunixin meglumine (P = 0.014). Both drugs inhibited the COX-2 prostanoid PGE(2). There were no significant differences in pain scores between groups (P = 0.2). However, there was a 3.23-fold increased risk (P = 0.04) of increased plasma sCD14 in horses treated with flunixin meglumine, a validated biomarker of equine endotoxaemia. MAIN LIMITATIONS: Horses were all treated with flunixin meglumine prior to referral. In addition, many horses were treated with lidocaine, which has been shown to mitigate the deleterious effects of flunixin meglumine. CONCLUSIONS: In SISO cases, firocoxib reduced a biomarker of endotoxaemia as compared with flunixin meglumine while continuing to provide similar levels of pain control.

Postoperative ileus (POI) is a serious condition which any horse undergoing abdominal surgery is at risk of developing, leading to increased hospitalisation time and resulting costs. Advances in the understanding of the development of equine POI are mainly based on human and rodentliterature, where manipulation-induced inflammation has been identified as a key trigger, with activation of resident muscularis externa macrophages playing a crucial role in the pathophysiology. Despite many pharmacological trials in all species, there is no single completely successful treatment for POI, highlighting that the condition is multifactorial in cause and requires a multimodal approach to minimise its incidence.

Intestinal ischemia remains a major cause of morbidity and mortality in human and veterinary patients. Many disease processes result in intestinal ischemia, when the blood supply and therefore oxygen is decreased to the intestine. This leads to intestinal barrier loss and damage to the underlying tissue. Intestinal stem cells reside at the base of the crypts of Lieberkuhn and are responsible for intestinal renewal during homeostasis and following injury. Ex vivo cell culture techniques have allowed for the successful study of epithelial stem cell interactions by establishing culture conditions that support the growth of three-dimensional epithelial organ-like systems (termed "enteroids" and "colonoids" from the small and large intestine, respectively). These enteroids are composed of crypt and villus-like domains and mature to contain all of the cell types found within the epithelium. Historically, murine models have been utilized to study intestinal injury. However, a porcine model offers several advantages including similarity of size as well as gastrointestinal anatomy and physiology to that of humans. By utilizing a porcine model, we establish a protocol in which segmental loops of intestinal ischemia can be created within a single animal, enabling the study of differing time points of ischemic injury and repair in vivo. Additionally, we describe a method to isolate and culture the intestinal stem cells from the ischemic loops of intestine, allowing for the continued study of epithelial repair, modulated by stem cells, ex vivo.

Type III interferons (IFNs) play a vital role in maintaining the antiviral state of the mucosal epithelial surface in the gut, and in turn, enteric viruses may have evolved to evade the type III IFN responses during infection. To study the possible immune evasion of the type III IFN response by porcine epidemic diarrhea virus (PEDV), a line of porcine intestinal epithelial cells was developed as a cell model for PEDV replication. IFN-λ1 and IFN-λ3 inhibited PEDV replication, indicating the anti-PEDV activity of type III IFNs. Of the 21 PEDV proteins, nsp1, nsp3, nsp5, nsp8, nsp14, nsp15, nsp16, open reading frame 3 (ORF3), E, M, and N were found to suppress type III IFN activities, and IRF1 (interferon regulatory factor 1) signaling mediated the suppression. PEDV specifically inhibited IRF1 nuclear translocation. The peroxisome is the innate antiviral signaling platform for the activation of IRF1-mediated IFN-λ production, and the numbers of peroxisomes were found to be decreased in PEDV-infected cells. PEDV nsp1 blocked the nuclear translocation of IRF1 and reduced the number of peroxisomes to suppress IRF1-mediated type III IFNs. Mutational studies showed that the conserved residues of nsp1 were crucial for IRF1-mediated IFN-λ suppression. Our study for the first time provides evidence that the porcine enteric virus PEDV downregulates and evades IRF1-mediated type III IFN responses by reducing the number of peroxisomes. IMPORTANCE Porcine epidemic diarrhea virus (PEDV) is a highly contagious enteric coronavirus that emerged in swine in the United States and has caused severe economic losses. PEDV targets intestinal epithelial cells in the gut, and intestinal epithelial cells selectively induce and respond to the production of type III interferons (IFNs). However, little is known about the modulation of the type III IFN response by PEDV in intestinal epithelial cells. In this study, we established a porcine intestinal epithelial cell model for PEDV replication. We found that PEDV inhibited IRF1-mediated type III IFN production by decreasing the number of peroxisomes in porcine intestinal epithelial cells. We also demonstrated that the conserved residues in the PEDV nsp1 protein were crucial for IFN suppression. This study for the first time shows PEDV evasion of the type III IFN response in intestinal epithelial cells, and it provides valuable information on host cell-virus interactions not only for PEDV but also for other enteric viral infections in swine.

Intestinal ischemic injury results sloughing of the mucosal epithelium leading to host sepsis and death unless the mucosal barrier is rapidly restored. Neonatal necrotizing enterocolitis (NEC) and volvulus in infants is associated with intestinal ischemia, sepsis and high mortality rates. We have characterized intestinal ischemia/ repair using a highly translatable porcine model in which juvenile (6-8-week-old) pigs completely and efficiently restore barrier function by way of rapid epithelial restitution and tight junction re-assembly. In contrast, separate studies showed that younger neonatal (2-week-old) pigs exhibited less robust recovery of barrier function, which may model an important cause of high mortality rates in human infants with ischemic intestinal disease. Therefore, we aimed to further refine our repair model and characterize defects in neonatal barrier repair. Here we examine the defect in neonatal mucosal repair that we hypothesize is associated with hypomaturity of the epithelial and subepithelial compartments. Following jejunal ischemia in neonatal and juvenile pigs, injured mucosa was stripped from seromuscular layers and recovered ex vivo while monitoring transepithelial electrical resistance (TEER) and 3H-mannitol flux as measures of barrier function. While ischemia-injured juvenile mucosa restored TEER above control levels, reduced flux over the recovery period and showed 93±4.7% wound closure, neonates exhibited no change in TEER, increased flux, and a 11±23.3% increase in epithelial wound size. Scanning electron microscopy revealed enterocytes at the wound margins of neonates failed to assume the restituting phenotype seen in restituting enterocytes of juveniles. To attempt rescue of injured neonatal mucosa, neonatal experiments were repeated with the addition of exogenous prostaglandins during ex vivo recovery, ex vivo recovery with full thickness intestine, in vivo recovery and direct application of injured mucosal homogenate from neonates or juveniles. Neither exogenous prostaglandins, intact seromuscular intestinal layers, nor in vivo recovery enhanced TEER or restitution in ischemia-injured neonatal mucosa. However, ex vivo exogenous application of injured juvenile mucosal homogenate produced a significant increase in TEER and enhanced histological restitution to 80±4.4% epithelial coveragein injured neonatal mucosa. Thus, neonatal mucosal repair can be rescued through direct contact with the cellular and non-cellular milieu of ischemia-injured mucosa from juvenile pigs. These findings support the hypothesis that a defect in mucosal repair in neonates is due to immature repair mechanisms within the mucosal compartment. Future studies to identify and rescue specific defects in neonatal intestinal repair mechanisms will drive development of novel clinical interventions to reduce mortality in infants affected by intestinal ischemic injury.

Summary Reasons for performing study A recent survey of European Colleges (European College of Equine Internal Medicine [ECEIM] and European College of Veterinary Surgeons [ECVS]) revealed the different strategies implemented by, and some of the challenges facing, European clinicians presented with cases of post operative ileus (POI). It was concluded that further comparative analysis of opinions, canvassed from additional colleges of equine veterinary specialism worldwide, would provide valuable additional insight into current POI knowledge on a more global scale. Objectives To report and compare the current strategies favoured by American veterinary specialists when managing POI in horses that underwent emergency colic surgery. Study design Cross-sectional survey. Methods Electronic invitations were sent to 814 Large Animal specialists, including 3 colleges: the American College of Veterinary Internal Medicine (ACVIM), American College of Veterinary Surgeons (ACVS) and the American College of Veterinary Emergency and Critical Care (ACVECC). Results The response rate was 14% (115/814). The majority of respondents (68%) reported an estimated prevalence range of POI of 0–20%. The presence of reflux on nasogastric intubation was the main criterion used to define POI. A lesion involving the small intestine was considered the main risk factor for POI. Anti-inflammatory drugs, intravenous (i.v.) fluids and antimicrobial drugs were the primary strategies used when managing POI. Flunixin meglumine and i.v. lidocaine were the drugs most commonly used in the treatment of horses with POI. Supplementary management strategies targeted mainly the prevention of post operative adhesions, infection and inflammation. Conclusions There is a lack of consensus on the clinical definition of POI. Prospective and objective clinical assessment of the effectiveness of the different strategies contained within this and the European survey is necessary in order to identify a standardised approach to the management of equine POI.

Summary Reasons for performing study Back pain is a common cause of gait alterations and poor performance in horses, but the available imaging modalities are frequently insufficient to isolate the underlying pathology. In human patients, epidural endoscopy (epiduroscopy) is successfully used to diagnose and treat challenging cases of lower back pain. Endoscopy of the cervical epidural space has previously been reported in anaesthetised horses. Objectives To develop a technique for lumbosacral epiduroscopy in standing horses and to describe the endoscopic anatomy of the lumbosacral epidural space. Study design Pilot study to assess the feasibility of lumbosacral epiduroscopy in 5 horse cadavers. Methods The cadavers of 5 horses, weighing 457–694 kg (mean, 570 kg), were suspended in an upright position. Vascular dilators of increasing size were inserted between the first 2 moveable vertebrae caudal to the sacrum to create a minimally invasive approach into the epidural space. A flexible videoendoscope was introduced and advanced as far cranially as the length of the endoscope permitted. The lumbosacral epidural space underwent gross necropsy examination following the procedure. Results The endoscope was successfully inserted into the epidural space in all horses. Saline injection through the working channel of the endoscope allowed the following anatomical structures to be seen: dura mater, left and right lumbosacral spinal nerves, cauda equina, epidural fat, connective tissue and blood vessels. Using the 60 cm working length of the endoscope, the epidural space could be examined as far cranial as L3–T18, depending on the size of the horse. No gross damage to epidural neurovascular structures was observed on necropsy examination. Conclusion Lumbosacral epiduroscopy is technically feasible in standing horses and may become a valuable diagnostic tool in horses with caudal back or limb pain of unknown origin. Studies in live horses will be necessary to evaluate the safety of the procedure.

There is increasing interest in non-rodent translational models for the study of human disease. The pig, in particular, serves as a useful animal model for the study of pathophysiological conditions relevant to the human intestine. This review assesses currently used porcine models of gastrointestinal physiology and disease and provides a rationale for the use of these models for future translational studies. The pig has proven its utility for the study of fundamental disease conditions such as ischemia/ reperfusion injury, stress-induced intestinal dysfunction, and short bowel syndrome. Pigs have also shown great promise for the study of intestinal barrier function, surgical tissue manipulation and intervention, as well as biomaterial implantation and tissue transplantation. Advantages of pig models highlighted by these studies include the physiological similarity to human intestine as well as to mechanisms of human disease. Emerging future directions for porcine models of human disease include the fields of transgenics and stem cell biology, with exciting implications for regenerative medicine.

Ischemia–reperfusion (IR) injury of the intestine occurs when blood flow is temporarily interrupted, which occurs during interventions such as surgery for an abdominal aortic aneurysm, small bowel transplantation, strangulating hernias, and neonatal necrotizing enterocolitis. It can also occur as a result of collapse of the systemic circulation during conditions such as hemorrhagic shock following trauma, septic shock, or heat stress [1]. At the cellular level, the initial intestinal ischemic injury reduces cellular mitochondrial ATP generation, activates hydrolases, reduces cell membrane selective permeability, and increases calcium influx into ischemic cells. Reperfusion may exacerbate the extent of injury through the activation of an intense systemic inflammatory response [2] such as marked pro-inflammatory cytokine release, production of reactive oxygen species (ROS), increased expression of nitric oxide (NO), Toll-like receptor (TLR)-4 signaling, and activation of inflammatory transcription factors, among other pro-inflammatory mechanisms [3]. IR injury is therefore difficult to manage clinically with consequent high morbidity and mortality [4]. Ischemic preconditioning is an alternative strategy to reduce IR injury among therapeutic interventions aimed at reducing IR injury by inhibiting the activation of inflammatory cells [4]. Ischemic preconditioning consists of a brief episode of ischemia preceding the major ischemic event, an intervention that activates tissue-adaptive mechanisms. Ischemic preconditioning can be induced mechanically or pharmacologically; mechanical preconditioning, in which the target organ is exposed to a brief ischemic episode by mechanically compromising its blood supply prior to prolonged ischemia, has the benefit of reducing IR injury, but it has the principal disadvantage of traumatizing major vessels and stressing the target organ. Alternatively, the identification of the signaling pathways underlying ischemic preconditioning has created the possibility of using pharmacological agents that confer protection against IR injury [5]. Ischemic preconditioning increases the generation of endogenous antioxidants such as glutathione, superoxide dismutase, and hemoxygenase-1 (HO-1). Nuclear transcription factors such as nuclear factor-kappa B (NFjB) and NO are also affected by ischemic preconditioning, reducing the generation of pro-inflammatory cytokines, and preserving blood flow, oxygenation, and mitochondrial function [3, 6]. Clinically, ischemic preconditioning may be applied to patients prior to a planned surgical procedure such as cardiac, hepatic, or pulmonary surgery, in order to reduce the potential adverse effects of IR injury in the postoperative period. In this issue of Digestive Diseases and Sciences, Liu et al. [7] report that ischemic preconditioning-induced suppressor of cytokine signaling-1 (SOCS-1) activation protects the intestine from IR injury via downregulation of the Toll-like receptor 4 (TLR4) pathway (Fig. 1). Among the molecular mechanisms integral to the pathogenesis of IR injury, the authors focused on TLR4 signaling and its downstream signaling intermediate tumor necrosis factor receptor-associated factor 6 (TRAF6), which has been understudied in IR injury. Additionally, the investigators also studied the contribution of receptor interacting protein 1 (RIP1), a key regulator of cellular apoptosis, regulated by tumor necrosis factor (TNF) signaling. SOCS-1 is a key regulator of inflammatory responses, including the TLR4 signaling pathway, thereby putatively inhibiting & Anthony T. Blikslager anthony_blikslager@ncsu.edu

SummaryBackground Progenitor cells play critical roles in epithelial repair following ischaemic injury. Protein biomarkers have been used to identify intestinal progenitor cell subpopulations. This study aims to determine if a critical number of intestinal progenitor cells can predict tissue viability and survival to discharge of large colon volvulus (LCV) cases. Objectives The objectives were to 1) identify intestinal progenitor cell subpopulations using biomarkers: proliferating cell nuclear antigen (PCNA), sex determining region Y box 9 (SOX9), phospho-histone H3 (PHH3) and Ki-67, 2) define cut-off values for critical numbers of positive cells and 3) determine if survival to discharge is associated with cut-off values. Study design Retrospective cohort study. Methods Adult horses admitted to the Farm and Equine Veterinary Medical Center at NC State's Veterinary Hospital and Peterson and Smith Equine Hospital between 2006 and 2016 that underwent an exploratory coeliotomy with a diagnosis of LCV of ≥360 degrees, had pelvic flexure biopsy and that recovered from general anaesthesia were selected for inclusion in the study. Immunohistochemical analyses were performed and positive cells were counted. Optimal cut-off values were determined using receiver operator curves. A Fisher's exact test was used to associate cut-off values with survival to discharge. Results In this study, 23 cases of LCV ≥360° were included. Of 23 horses, 13 (57%) survived to discharge. A cut-off value of

Within this issue of Neurogastroenterology and Motility, an article by Pohl et al highlights new insights from a powerful porcine model of the link between early life adversity and relapsing functional gastrointestinal disorders. Early weaning stress closely mimics the early life psychosocial stressors that have been linked to adult onset gastrointestinal dysfunction. This early weaning model provides reproducible and highly translatable outcomes in young stress-challenged pigs. Due to the convincingly comparable neurological and gastroenterological anatomy and physiology between pigs and human beings, gastrointestinal stress and injury studies utilizing swine models will provide invaluable insights to improve our understanding and treatment of gastrointestinal disease in human beings. Future studies to examine mechanisms underlying this link between early life adversity and functional gastrointestinal disorders will explore the roles of gender and hypo-maturity in gastrointestinal responses to stress.

Nonsteroidal anti-inflammatory drugs work through inhibition of cyclooxygenase (COX) and are highly effective for the treatment of pain and inflammation in horses. There are 2 clinically relevant isoforms of COX. Cyclooxygenase-1 is constitutively expressed and is considered important for a variety of physiologic functions, including gastrointestinal homeostasis. Thus, NSAIDs that selectively inhibit COX-2 while sparing COX-1 may be associated with a lower incidence of adverse gastrointestinal effects. Various formulations of firocoxib, a COX-2-selective NSAID, labeled for use in horses are available in the United States. Equine practitioners should know that the FDA limits the use of firocoxib to formulations labeled for horses, regardless of price concerns. In addition, practitioners will benefit from understanding the nuances of firocoxib administration, including the importance of correct dosing and the contraindications of combining NSAIDs. Together with knowledge of the potential advantages of COX-2 selectivity, these considerations will help veterinarians select and treat patients that could benefit from this new class of NSAID.

Objective To review the physiology of the cyclooxygenase (COX) enzymes with reference to the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) related to their analgesic and antiendotoxic properties as well as the mechanisms responsible for adverse gastrointestinal, renal, and coagulation effects. Data Sources Human and veterinary peer reviewed literature Veterinary Data Synthesis NSAIDs are frequently administered to critically ill horses for their analgesic and anti-inflammatory effects. However, NSAIDs have significant side effects principally on the gastrointestinal mucosa and kidneys. These side effects may be exacerbated in critically ill horses if they have gastrointestinal damage or are volume depleted Conclusions This review provides important information for equine veterinarians and criticalists on the advantages and disadvantages of using traditional NSAIDs and newer equine COX-2 selective NSAIDs for the management of different conditions in critically ill horses.