Stored at 80C until analysis.cute mesenteric ischemia is caused by a critical Topoisomerase reduction in intestinal blood flow that frequently results in bowel necrosis and is associated with a high mortality . Intestinal ischemia reperfusion is encountered in a variety of clinical conditions, such as hemorrhagic shock, strangulationobstruction of the intestine, sepsis, vascular surgery, small bowel transplantation, cardiopulmonary bypass, or abdominal aortic surgery . IR of the intestine can result in a systemic response; common clinical features caused by intestinal impaired blood perfusion include bacterial translocation, systemic inflammatory response syndrome, acute lung injury, or multiple organ failure .
Although intestinal ischemia and hypoxia result in hypoxiainduced inflammation , hypoxia also drives hypoxiaassociated antiinflammatory responses, particularly through changes in gene expression coordinated by the transcription factor hypoxiainducible factor 1 . As an important regulator of oxygen homeostasis, HIF1 Dexrazoxane has been implicated in transcriptional regulation of antiinflammatory or tissueprotective–signaling pathways . For example, HIF1 coordinates the production and signaling properties of extracellular adenosine . Specifically, HIF1a has been implicated in the coordinated induction of ecto59nucleotidase —the pacemaker enzyme of extracellular adenosine production —and the A2B adenosine receptor . Moreover, CD73 and A2BAR have been implicated in intestinal protection from ischemia or inflammation .
Based on our previous studies showing protection from extracellular adenosine generation and A2BAR signaling in intestinal IR, we hypothesized that HIF represents a potential therapeutic target through its effects on CD73 and the A2BAR. Consistent with this hypothesis, we provide evidence eukaryotic for a protective role of hypoxiadependent– signaling pathways during mucosal IR injury involving HIFdependent enhancement of purinergicsignaling pathways.the key enzyme in extracellular adenosine production, in attenuating intestinal IRmediated injury . CD73 is induced by ambient exposure to hypoxia or following mesenteric ischemia . Moreover, HIF was suggested to enhance adenosinesignaling events on the receptor level . Similarly, adenosineclearance mechanisms, such as those involving equilibrative nucleoside transporters, are repressed during hypoxia through HIF1–dependent mechanisms, thereby lengthening the apparent halflife of extracellular adenosine .
Equilibrative nucleoside transporters were shown to be present in murine and human intestine . We also previously demonstrated that A2BAR signaling provides potent protection during intestinal IR ; in the current study, we extended these findings and showed that A2BAR is an important signaling end point in HIFdependent gut protection. Genetic studies to address the role of HIF1 in human diseases are complicated by the fact that genetic deletion of HIF1a results in embryonic lethality . Therefore, Karhausen generated a mouse line with intestinal epitheliumtargeted deletion of HIF1a. Similar to the present findings of HIF1–dependent protection from intestinal IR injury, studies of murine colitis in conditional HIF1a2 2 mice revealed that decreased HIF1 expression correlated with more severe clinical .