In the absence of antibodies, Cox 2 transcription is not up-regulated and the production of PGE2, another required component for IR-induced damage, is not increased [27]. organs as a result of various insults, such as trauma, shock, routine medical procedures and organ transplantation. The intestinal mucosa is among the organs most sensitive to IR (reviewed in [1]) with acute mesenteric arterial or venous thrombosis, embolism, and obstruction being common causes of intestinal IR (reviewed in [2,3]). Cases of acute mesenteric ischemia are classified by cause. In order of incidence, they are arterial embolism, arterial thrombus, non-occlusive and venous thrombosis (reviewed in [2]). Symptoms are non-specific and can be subtle, resulting in a delay of correct diagnosis which decreases survival probability. Furthermore, common sequelae AGN-242428 include acute lung injury and multiple organ failure. Bowel resection is usually indicated in most cases which leaves surviving patients with bowel problems, such as short bowel syndrome, for the AGN-242428 remainder of their lives. Despite decades of improved imaging devices and medical advances, the mortality rate associated with intestinal IR remains at 50 to 80% (reviewed in [4]). The mesenteric arteries can maintain adequate perfusion of the intestine over a broad range of blood pressures, however below 40 to 45 mm Hg, perfusion is compromised (reviewed in [3]). The gastrointestinal tract has a very high capillary density, many collateral vessels and receives approximately 25% of total cardiac output at rest (reviewed in [3]). Cellular injury in humans is usually detectable by 20 minutes of total ischemia and within 60 minutes in the case of partial ischemia (reviewed in [3]). Rodents are commonly used as research models for intestinal IR and have provided a large knowledge base regarding associated physiology and pathogenesis. Studies in mice have shown changes in the internal pH of enterocytes, abruptly increasing from 6.8 to 7.1 at the initiation of ischemia, and rapidly stabilizing AGN-242428 at a pH of 6.3 by three minutes into ischemia [1]. Upon reperfusion, cascades of cellular events lead to eicosanoid production, signaling molecules derived from 20 carbon fatty acids via oxidation, formation AGN-242428 of reactive oxygen species, secretion of cytokines and activation of the innate immune response. The barrier between luminal contents and intestinal mucosa is usually compromised as enterocytes are shed, by necrosis and apoptosis, and capillary permeability increases [57] (Fig. 1). The duration of ischemia influences the severity of damage and mortality. A recent study with mice exhibited increasing severity of tissue damage, as assessed by histology, with increasing duration of ischemia [8]. Furthermore, mice AGN-242428 subjected to 30 and 35 minutes of ischemia survived a minimum of 18 hours while mice subjected to 40 and 45 minutes of ischemia all succumbed within six hours post ischemia [8]. In contrast, experimental models of intestinal IR in horses frequently utilize two hours of ischemia and horses survive for 18 hours of reperfusion [911]. In fact, 10 of 11 horses subjected to two hours of jejunal ischemia survived 10 days, to the studys end-point [12]. Thus, the duration of ischemia tolerated varies between species. == Physique 1. Factors contributing to IR-induced tissue damage. == The pathogenesis of IR-induced injury is complex with many contributing factors. Shown are a few of the factors involved. Several factors contributing to IR-induced pathology will be discussed briefly; however, the majority of this review will focus on Rabbit Polyclonal to CYTL1 lipids, neo-antigens and phosopholipid scramblase 1 as they relate to IR-induced pathology. Eicosanoids, derivatives of arachidonic acid, are rapidly produced during the reperfusion period. Prostaglandin E2(PGE2) was found to be required but not sufficient for tissue damage in a mouse model of intestinal IR [13]. The conversion of arachidonic acid (AA) to prostaglandins requires the cyclooxygenase (Cox) enzymes. It is well established that this expression of Cox 2, the inducible isoform, is usually elevated in the intestinal tissue following ischemia. Several animal models have exhibited an increase in Cox 2 transcription and translation in the intestine following varying lengths of ischemia and reperfusion [1318]. The use of Cox inhibitors, NS-398 and FK3311, has further exhibited the importance of this pathway in reperfusion injury.