Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

Hypoxia, a common feature within many types of solid tumors, is known to be closely associated with limited efficacy for cancer therapies, including radiotherapy (RT) in which oxygen is essential to promote radiation-induced cell damage. Here, an artificial nanoscale red-blood-cell system is designed by encapsulating perfluorocarbon (PFC), a commonly used artificial blood substitute, within biocompatible poly(d,l-lactide-co-glycolide) (PLGA), obtaining PFC@PLGA nanoparticles, which are further coated with a red-blood-cell membrane (RBCM). The developed PFC@PLGA-RBCM nanoparticles with the PFC core show rather efficient loading of oxygen, as well as greatly prolonged blood circulation time owing to the coating of RBCM. With significantly improved extravascular diffusion within the tumor mass, owing to their much smaller nanoscale sizes compared to native RBCs with micrometer sizes, PFC@PLGA-RBCM nanoparticles are able to effectively deliver oxygen into tumors after intravenous injection, leading to greatly relieved tumor hypoxia and thus remarkably enhanced treatment efficacy during RT. This work thus presents a unique type of nanoscale RBC mimic for efficient oxygen delivery into solid tumors, favorable for cancer treatment by RT, and potentially other types of therapy as well.

Erythrocyte-Membrane-Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy.

Level 1: Evidence obtained from systematic reviews of all relevant randomized controlled trials. Level 2: Evidence derived from at least one properly designed randomized controlled trial. Level 3: Evidence from a well-designed control trial without randomization; or from well-designed cohort or case–control analytical studies; preferably from more than one center or research group; or from multiple time series with or without intervention. Level 4: Opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees.This level signifies the need for further research. The final document was prepared and submitted to the Secretary General of OMGE for final scrutiny prior to publication for the World Congress of Gastroenterology. At the congress the recommendations were presented and questions and comments noted. These comments were incorporated into the final guidelines where appropriate.

Guidelines for the management of acute pancreatitis.

Ferroptosis is a recently identified form of regulated cell death defined by the iron-dependent accumulation of lipid reactive oxygen species. Ferroptosis has been studied in various diseases such as cancer, Parkinson’s disease, and stroke. However, the exact function and mechanism of ferroptosis in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. Considering the unique conditions required for ferroptosis, we hypothesize that ischemia promotes ferroptosis immediately after intestinal reperfusion. In contrast to conventional strategies employed in I/R studies, we focused on the ischemic phase. Here we verified ferroptosis by assessing proferroptotic changes after ischemia along with protein and lipid peroxidation levels during reperfusion. The inhibition of ferroptosis by liproxstatin-1 ameliorated I/R-induced intestinal injury. Acyl-CoA synthetase long-chain family member 4 (ACSL4), which is a key enzyme that regulates lipid composition, has been shown to contribute to the execution of ferroptosis, but its role in I/R needs clarification. In the present study, we used rosiglitazone (ROSI) and siRNA to inhibit ischemia/hypoxia-induced ACSL4 in vivo and in vitro. The results demonstrated that ACSL4 inhibition before reperfusion protected against ferroptosis and cell death. Further investigation revealed that special protein 1 (Sp1) was a crucial transcription factor that increased ACSL4 transcription by binding to the ACSL4 promoter region. Collectively, this study demonstrates that ferroptosis is closely associated with intestinal I/R injury, and that ACSL4 has a critical role in this lethal process. Sp1 is an important factor in promoting ACSL4 expression. These results suggest a unique and effective mechanistic approach for intestinal I/R injury prevention and treatment.

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Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion.

The ischemia-reperfusion injury,which is called I/R,is an important problem in the surgical practices.It plays an important role in the developing of pathology,such as the small intestine transplantation,the serious infection,the wound,the shock,the cardiorespiratory functional defeat.The consequence of intestinal I/R,not only causes partial histologic lesion of intestinal mucosa,more over may cause intestinal bacteria colony shifting,changes the intestines absorption function,as well as damages to the distance organ,even leads to the multi-systems organ function defect syndrome.This article explained its mechanism and prevention measure for the past few years and hoped to provide the basis for the future clinical work.

Ischemia-Reperfusion Injury of the Intestine and Protective Strategies Against Injury

Ischemia-reperfusion injury of the intestine is a significant problem in abdominal aortic aneurysm surgery, small bowel transplantation, cardiopulmonary bypass, strangulated hernias, and neonatal necrotizing enterocolitis. It can also occur as a consequence of collapse of systemic circulation, as in hypovolemic and septic shock. It is associated with a high morbidity and mortality. This article is a comprehensive review of the current status of the molecular biology and the strategies to prevent ischemia-reperfusion injury of the intestine. Various treatment modalities have successfully been applied to attenuate reperfusion injury in animal models of reperfusion injury of the intestine. Ischemic preconditioning has been found to be the most promising strategy against reperfusion injury during the last few years, appearing to increase the tolerance of the intestine to reperfusion injury. Although ischemic preconditioning has been shown to be beneficial in the human heart and the liver, prospective controlled studies in humans involving ischemic preconditioning of the intestine are lacking. Research focused on the application of novel drugs that can mimic the effects of ischemic preconditioning to manipulate the cellular events during reperfusion injury of the intestine is required.

Ischemia-reperfusion injury of the intestine and protective strategies against injury

Most cases of pancreatitis are mild and selflimited. On the other hand, approximately one quarter of patients with pancreatitis may develop vascular complications. Vascular complications in pancreatitis are well recognized. Their exact incidence is not known. The most common complications are haemorrhage into a pseudocyst, erosions of the upper gastrointestinal arteries, thromboses of the portal venous system, formation of varices or pseudoaneurysms and rupture of a pseudoaneurysm. Pancreatitis in combination with vascular complications is dangerous and potentially lethal. The survival of patients with pancreatitis and vascular complications depends on the early diagnosis of these complications. This article focuses on the aetiology, presentation, recent developments in diagnosis and management of such complications.

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Vascular complications of pancreatitis

Background:

Ischaemia–reperfusion (IR) injury of the intestine occurs commonly during abdominal surgery. Ischaemic preconditioning (IPC) provides a way of protecting the organ from damage inflicted by IR. This study was designed to evaluate the beneficial effect of IPC, focusing on the intestinal microcirculation and oxygenation in intestinal IR injury.



Methods:

Rats were allocated to three groups. Animals in the IR and IPC groups underwent 30 min of intestinal ischaemia followed by 2 h of reperfusion. In the IPC group this was preceded by 10 min of ischaemia and 10 min of reperfusion. Animals in the third group underwent laparotomy but no vascular occlusion. Intestinal microvascular perfusion, oxygenation and portal venous blood flow (PVF) were monitored continuously. At the end of the reperfusion period, blood samples were obtained for measurement of lactate dehydrogenase (LDH) and biopsies of ileum for histological evaluation.



Results:

IPC improved intestinal microvascular perfusion and tissue oxygenation significantly at the end of the reperfusion period (P < 0·001). PVF improved significantly in the IPC compared with the IR group (P = 0·005). The serum LDH concentration was significantly lower in the IPC than the IR group (mean(s.e.m.) 667·1(86·8) versus 1973·8(306·5) U/l; P < 0·001) Histological examination showed that ileal mucosa was significantly less injured in the IPC group.



Conclusions:

This study demonstrated that IPC improves intestinal microvascular perfusion and oxygenation. Copyright © 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Ischaemic preconditioning improves microvascular perfusion and oxygenation following reperfusion injury of the intestine

Objective: The small bowel villi are extremely sensitive to ischemia–reperfusion (IR) injury and a range of microcirculatory disturbances contribute to structural and functional changes. The aim of this study was to determine the protective effects of ischemic preconditioning (IPC) of the intestine on the mucosal villous microcirculation during IR injury of the intestine and whether heme oxygenase (HO) is involved in the protection.Methods: Rats were allocated into 4 groups: () sham, () IR consisting of 30 min of ischemia followed by 2 h of reperfusion, () IPC, as in IR group, but preceded by 10 min of ischemia and 10 min of reperfusion, and () with administration of zinc protoporphyrin, an HO inhibitor before IPC and IR. The mucosa of an exteriorized segment of ileum was visualized. Mucosal perfusion index (MPI), red blood cell (RBC) velocity and leukocyte–endothelial interactions during reperfusion were assessed continuously using in vivo fluorescence microscopy. HO activity in the ileum was assessed at...

Protective Effects of Ischemic Preconditioning on the Intestinal Mucosal Microcirculation Following Ischemia–Reperfusion of the Intestine

Background Ischemia and reperfusion (IR) injury of the intestine is a major cause of morbidity and mortality following small bowel transplantation. The current study evaluates the effect of ischemic preconditioning (IPC) on the intestinal microcirculation in the late phase of IR injury of the intestine. Methods Sixty rats were randomly allocated to 5 study groups (n = 12 per group): (1) sham, (2) IR (3) IPC, (4) pyrrolidine dithiocarbamate (PDTC) (HO-1 inducer), and (5) zinc protoporhyrin (ZnPP) (HO-1 inhibitor). Mucosal perfusion and leukocyte–endothelial interactions were measured with the aid of an intravital microscope. At the end of the experiments, blood samples for lactate dehydrogenase (LDH) levels and biopsies of ileum for histologic evaluation were obtained. Results IPC significantly improved the mucosal perfusion and decreased the leukocyte–endothelial interactions. Histologic examination showed that ileal mucosa was significantly less injured in the IPC and PDTC groups as compared with the IR group. Conclusions IPC protects the intestine from late reperfusion injury. HO-1 is involved in this protection. These findings may be of significant importance in clinical small bowel transplantation.

IH Mallick

Papers

Ischemia-reperfusion injury of the intestine and protective strategies against injury

Vascular complications of pancreatitis

Ischaemic preconditioning improves microvascular perfusion and oxygenation following reperfusion injury of the intestine

Protective Effects of Ischemic Preconditioning on the Intestinal Mucosal Microcirculation Following Ischemia–Reperfusion of the Intestine

Ischemic preconditioning of small bowel mitigates the late phase of reperfusion injury: heme oxygenase mediates cytoprotection