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Intestinal ischemia-reperfusion (IR) injury is a frequent, but potentially life-threatening condition. Although much has been learned about its pathophysiology from animal IR models, the translation to the human setting is imperative for better understanding of its etiology. This could provide us with new insight into development of early detection and potential new therapeutic strategies. Over the past decade, we have studied the pathophysiology of human small intestinal and colonic ischemia-reperfusion (IR) in newly developed human in vivo IR models. In this review, we give an overview of new insights on the sequelae of human intestinal IR, with particular attention for the differences in histopathology between small intestinal and colonic IR.

Aim: To assess intestinal barrier function during human intestinal ischemia and reperfusion (IR)., Methods: In a human experimental model, 6 cm of jejunum was selectively exposed to 30 min of ischemia (I) followed by 30 and 120 min of reperfusion (R). A sham procedure was also performed. Blood and tissue was sampled at all-time points. Functional barrier function was assessed using dual-sugar absorption tests with lactulose (L) and rhamnose (R). Plasma concentrations of citrulline, an amino acid described as marker for enterocyte function were measured as marker of metabolic enterocytes restoration. Damage to the epithelial lining was assessed by immunohistochemistry for tight junctions (TJs), by plasma marker for enterocytes damage (I-FABP) and analyzed by electron microscopy (EM) using lanthanum nitrate as an electrondense marker., Results: Plasma L/R ratio's were significantly increased after 30 min of ischemia (30I) followed by 30 min of reperfusion (30R) compared to control (0.75 ± 0.10 vs 0.20 ± 0.09, P < 0.05). At 120 min of reperfusion (120R), ratio's normalized (0.17 ± 0.06) and were not significantly different from control. Plasma levels of I-FABP correlated with plasma L/R ratios measured at the same time points (correlation: 0.467, P < 0.01). TJs staining shows distortion of staining at 30I. An intact lining of TJs was again observed at 30I120R. Electron microscopy analysis revealed disrupted TJs after 30I with paracellular leakage of lanthanum nitrate, which restored after 30I120R. Furthermore, citrulline concentrations closely paralleled the histological perturbations during intestinal IR., Conclusion: This study directly correlates histological data with intestinal permeability tests, revealing that the human gut has the ability of to withstand short episodes of ischemia, with morphological and functional recovery of the intestinal barrier within 120 min of reperfusion., Competing Interests: Conflict-of-interest statement: No conflicts of interest exist.

Objective: To study the effects of COX-2 on colonic surgical wound healing., Background: Cyclooxygenase-2 (COX-2) is a key enzyme in gastrointestinal homeostasis. COX-2 inhibitors have been associated with colonic anastomotic leakage., Methods: Wildtype, COX-2 knockout and COX-2 heterozygous mice were subjected to a model of colonic anastomotic leakage, and were treated with vehicle, diclofenac, or prostaglandin E2 (PGE2), the most important COX-2 product in the intestine. We assessed anastomotic leakage, mortality, angiogenesis, and inflammation. Furthermore, we investigated the association between anastomotic leakage and a human polymorphism of the COX-2 gene resulting in low COX-2 levels., Results: Diclofenac, a nonsteroidal anti-inflammatory drug inhibiting COX-2, increased anastomotic leakage compared to vehicle-treated mice (100% vs 25%, respectively). Similarly, 92% of COX-2-deficient mice developed anastomotic leakage (P = 0.003) compared to WT. PGE2 partly rescued this severe phenotype because only 46% of PGE2-administered COX-2 knockout mice developed anastomotic leakage (P = 0.02). This may be related to decreased neovascularization, because decreased CD31 staining, indicating less blood vessels, was observed in COX-2 mice (2 vessels/mm vs 6 vessels/mm in controls (P = 0.03)). This effect could partly be reversed by administration of PGE2 to COX-2 mice. No significant differences in inflammation were found. PTGS2-765G>C polymorphism in humans, associated with reduced COX-2 expression, was associated with higher anastomotic leakage rates., Conclusions: COX-2-induced PGE2 production is essential for intestinal wound healing after colonic surgery, possibly via its effects on angiogenesis. These data emphasize that COX-2 inhibitors should be avoided after colonic surgery, and administration of PGE2 might be favorable for a selection of patients.

Early and accurate diagnosis of intestinal ischemia is important in order to provide rapid and correct treatment and reduce morbidity and mortality rates. Clinical signs and symptoms are often unspecific. This systemic review sums up literature regarding human plasma biomarkers for acute mesenteric ischemia reported during the last ten years. Classic, general markers, including lactate, white cell count, base excess, show poor diagnostic accuracy for intestinal ischemia. Preliminary results for ischemia-modified albumin are promising, which is also true for the inflammatory marker procalcitonin. Best diagnostic accuracy is described for D-dimer, a-Glutathione S-transferase (a-GST) and Intestinal fatty acid binding protein (I-FABP), reflecting coagulation activity and mucosal damage respectively. Future studies should be directed at phase four questions (Do patients who undergo the diagnostic test fare better (in their ultimate health outcomes) than similar patients who do not?) for these markers and the identification of additional, novel plasma biomarkers signaling various types and stages of intestinal ischemia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Aim of this study was to draw comparisons between human colonic and jejunal ischemia-reperfusion sequelae in a human in vivo experimental model., Background: In patients, colonic ischemia-reperfusion generally has a milder course than small intestinal ischemia-reperfusion. It is unclear which pathophysiologic processes are responsible for this difference., Methods: In 10 patients undergoing colonic surgery and 10 patients undergoing pancreaticoduodenectomy, 6 cm colon or jejunum was isolated and exposed to 60 minutes ischemia followed by various reperfusion periods. Morphology (hematoxylin and eosin), apoptosis (M30), tight junctions (zonula occludens 1), and neutrophil influx (myeloperoxidase) were assessed using immunohistochemistry. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were performed for interleukin-6 and tumor necrosis factor-α., Results: Hematoxylin and eosin staining revealed intact colonic epithelial lining, but extensive damage in jejunal villus tips after 60 minutes ischemia. After reperfusion, the colonic epithelial lining was not affected, whereas the jejunal epithelium was seriously damaged. Colonic apoptosis was limited to scattered cells in surface epithelium, whereas apoptosis was clearly observed in jejunal villi and crypts, (42 times more M30 positivity compared with colon, P < 0.01). Neutrophil influx and increased tumor necrosis factor-α mRNA expression were observed in jejunum after 30 and 120 minutes of reperfusion (P < 0.05). Interleukin-6 mRNA expression was increased in jejunum after 120 minutes of reperfusion (3.6-fold increase, P < 0.05), whereas interleukin-6 protein expression was increased in both colon (1.5-fold increase, P < 0.05) and small intestine (1.5-fold increase, P < 0.05) after 30 and 120 minutes of reperfusion., Conclusions: Human colon is less susceptible to IR-induced tissue injury than small intestine.

Background and Aim: Intestinal fatty acid-binding protein (I-FABP) is a useful marker in the detection of intestinal ischemia. However, more insight into the test characteristics of I-FABP release is needed. This study aimed to investigate the relationship between plasma I-FABP levels and the severity of ischemic mucosal injury, and define the clinical usefulness of systemic I-FABP following ischemia., Methods: In a human experimental model, 6 cm of the jejunum, to be removed for surgical reasons, was selectively exposed to either 15, 30, or 60 minutes of ischemia (I) followed by 30 and 120 minutes of reperfusion (R). Blood and tissue was sampled at all time points. Arteriovenous (V-A) concentration differences of I-FABP were measured. Tissue sections were stained with hematoxylin/eosin, and villus height was measured to score epithelial damage., Results: Histologic analysis showed only minor reversible intestinal damage following 15 I and 30 I; however, severe irreversible epithelial damage was observed in the jejunum exposed to 60 I. I-FABP V-A differences paralleled the degree of tissue damage over time [7.79 (± 1.8) ng/mL, 128.6 (± 44.2) ng/mL, 463.3 (± 139.8) ng/mL for 15 I, 30 I and 60 I, respectively]. A good correlation was found between histologic epithelial damage and V-A I-FABP (r=-0.82, P<0.001). Interestingly, systemic I-FABP levels were significantly increased after 60 I of this short small intestinal segment., Conclusions: This study demonstrates the relationship between the duration of ischemia and the extent of tissue damage, which is reflected by I-FABP V-A plasma levels. In addition, systemic I-FABP levels appear valuable in detecting irreversible intestinal ischemia-reperfusion damage.

Objectives: The main objective of this study was to evaluate the diagnostic accuracy of two novel biomarkers, calprotectin (CP) and serum amyloid A (SAA), along with the more traditional inflammatory markers C-reactive protein (CRP) and white blood cell count (WBC), in patients suspected of having acute appendicitis (AA). The secondary objective was to compare diagnostic accuracy of these biomarkers with a clinical scoring system and radiologic imaging., Methods: A total of 233 patients with suspected AA, presenting to the emergency department (ED) between January 2010 and September 2010, and 52 healthy individuals serving as controls, were included in the study. Blood was drawn and CP and SAA-1 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). CRP and WBC concentrations were routinely measured and retrospectively abstracted from the electronic health record, together with physical examination findings and radiologic reports. The Alvarado score was calculated as a clinical scoring system for AA. Final diagnosis of AA was based on histopathologic examination. The Mann-Whitney U-test was used for between-group comparisons. Receiver operating characteristic (ROC) curves were used to measure the diagnostic accuracy for the tests and to determine the best cutoff points., Results: Seventy-seven of 233 patients (33%) had proven AA. Median plasma levels for CP and SAA-1 were significantly higher in patients with AA than in those with another final diagnosis (CP, 320.9 ng/mL vs. 212.9 ng/mL; SAA-1, 30 mg/mL vs. 0.6 mg/mL; p < 0.001). CRP and WBC were significantly higher in patients with AA as well. The Alvarado score was helpful at the extremes (<3 or >7). Ultrasound (US) had a sensitivity of 84% and a specificity of 94%. Computed tomography (CT) had a sensitivity of 100% and a specificity of 91%. The area under the ROC (95% confidence interval [CI]) was 0.67 (95% CI = 0.60 to 0.74) for CP, 0.76 (95% CI = 0.70 to 0.82) for SAA, 0.71 (95% CI = 0.64 to 0.78) for CRP, and 0.79 (95% CI = 0.73 to 0.85) for WBC. No cutoff points had high enough sensitivity and specificity to accurately diagnose AA. However, a high sensitivity of 97% was shown at 7.5 × 10(9) /L for WBC and 0.375 mg/mL for SAA., Conclusions: CP, SAA-1, CRP, and WBC were significantly elevated in patients with AA. None had cutoff points that could accurately discriminate between AA and other pathology in patients with suspected AA. A WBC < 7.5 × 10(9) /L, with a low level of clinical suspicion for AA, can identify a subgroup of patients who may be sent home without further evaluation, but who should have available next-day follow-up., (© 2013 by the Society for Academic Emergency Medicine.)