Wenxuan Yang

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.

The contemporary role of antioxidant therapy in attenuating liver ischemia‐reperfusion injury: A review

Oxidative stress is an important factor in many pathological conditions such as inflammation, cancer, ageing and organ response to ischemia‐reperfusion. Humans have developed a complex antioxidant system to eliminate or attenuate oxidative stress. Liver ischemia‐reperfusion injury occurs in a number of clinical settings, including liver surgery, transplantation, and hemorrhagic shock with subsequent fluid resuscitation, leading to significant morbidity and mortality. It is characterized by significant oxidative stress but accompanied with depletion of endogenous antioxidants. This review has 2 aims: firstly, to highlight the clinical significance of liver ischemia‐reperfusion injury, the underlying mechanisms and the main pathways by which the antioxidants function, and secondly, to describe the new developments that are ongoing in antioxidant therapy and to present the experimental and clinical evidence about the role of antioxidants in modulating hepatic ischemia‐reperfusion injury. (Liver Transpl 2005;11:1031–1047.)

Impairment of Hepatic Microcirculation in Fatty Liver

Fatty liver or hepatic steatosis, which is the result of the abnormal accumulation of triacylglycerol within the cytoplasm of hepatocytes, is a common histological finding in human liver biopsy specimens that is attributed to the effects of alcohol excess, obesity, diabetes, or drugs. There is a general consensus that fatty liver compromises hepatic microcirculation, the common exchange network upon which hepatic arterial and portal inflows converge, regardless of underlying etiology. A significant reduction in hepatic microcirculation has been observed in human fatty donor livers and in experimental models of hepatic steatosis. There is an inverse correlation between the degree of fat infiltration and both total hepatic blood flow and flow in microcirculation. Fatty accumulation in the cytoplasm of the hepatocytes is associated with an increase in the cell volume that reduces the size of the hepatic sinusoid space by 50% compared with a normal liver and may result in partial or complete obstruction of the hepatic sinusoid space. As a result of impaired hepatic microcirculation, the hepatocytes of the fatty liver have reduced tolerance against ischemia‐reperfusion injury, which affects about 25% of the donors for liver transplantation because severe steatosis is associated with a high risk of primary nonfunction after liver transplantation.

The role of the insulin-like growth factor system in colorectal cancer : review of current knowledge

BackgroundThe insulin-like growth factor system, which includes insulin-like growth factors (IGF-I and IGF-II), IGF receptors (IGF-IR and IGF-IIR) and IGF binding proteins (IGFBPs), plays an important role in epithelial growth, anti-apoptosis and mitogenesis. There is a growing body of evidence showing that IGFs control growth and proliferation of several types of cancer. This review introduces the latest information on the biology of the IGF system and its pathophysiological role in the development of colorectal cancer.DiscussionThe growth promoting effects of IGF-I and IGF-II on cancer cells are mediated through the IGF-IR, which is a tyrosine kinase and cancer cells with a strong tendency to metastasise have a higher expression of the IGF-IR. Most of the IGFs in circulation are bound to the IGFBPs, which regulate the bioavailability of the IGFs. All IGFBPs inhibit IGF action by high affinity binding, while some of them also potentiate the effects of IGFs. Colon cancer cells produce specific proteases that degrade the IGFBP so that the IGF will be free to act on the cancer cell in an autocrine manner. Therefore, the IGFBPs play a crucial role in the development of the cancer.ConclusionThe current knowledge about the link between IGFs and colon cancer is mainly based on in vitro investigations. Further in vivo study is needed to understand the exact role of the IGF system, especially its binding proteins, so that they can be manipulated for the prevention and treatment of colorectal cancer.

The relationship of hepatic tissue oxygenation with nitric oxide metabolism in ischemic preconditioning of the liver

Ischemic preconditioning (IPC) may increase the hepatic tolerance of ischemic injury during liver surgery and transplantation via nitric oxide (NO) formation. This study investigates the effect of IPC on hepatic tissue oxygenation and the role of NO stimulation and inhibition on the preconditioning effect in the rat liver. Study groups had 1) sham laparotomy; 2) 45‐min lobar liver ischemia and 2‐h reperfusion (IR); 3) IPC with 5‐min ischemia and 10‐min reperfusion before IR; 4) L‐arginine before IR; and 5) Nω‐Nitro‐L‐arginine methyl ester (L‐NAME) + IPC before IR. Hepatic tissue oxygenation was monitored by near‐infrared spectroscopy. Plasma alanine aminotransferase and plasma nitrite/nitrate were measured. Following IR there was significant decrease in oxyhemoglobin and cytochrome oxidase and an increase in deoxyhemoglobin (P<0.05 vs. Sham). IPC produced a significant increase in intracellular oxygenation at the end of the reperfusion period (cytochrome oxidase CuA redox state, P<0.05 vs IR). NO stimulation with L‐arginine did not attenuate the impairment in hepatic tissue oxygenation after IR (P>0.05 vs IR). In contrast, inhibition of NO synthesis blocked the effect of IPC and further impaired tissue oxygenation (decreased cytochrome oxidase CuA redox state and increased deoxyhemoglobin, both P<0.05 vs IR), suggesting an aggravation of ischemia reperfusion injury. Hepatocellular injury was reduced by IPC and L‐arginine and increased by NO blockade with L‐NAME (Plasma ALT, all P< 0.05 vs IR). Hepatic tissue oxygenation correlated significantly with ALT and plasma nitrite/nitrate. Ischemic preconditioning significantly improved hepatic intra cellular oxygenation and reduced hepatocellular injury. NO stimulation reduced hepatocellular injury, whereas inhibition of nitric oxide synthesis blocked the effect of IPC and reduced tissue oxygenation and increased hepatocellular injury.

Nitric oxide synthase distribution and expression with ischemic preconditioning of the rat liver.

This study was undertaken to identify nitric oxide synthase (NOS) isoforms responsible for the generation of cytoprotective NO during liver ischemic preconditioning (IPC). Sprague‐Dawley rats were subjected to 45 min lobar ischemia followed by 2 h reperfusion. l‐arginine or Nω‐nitro‐l‐arginine methyl ester (L‐NAME) was administered to stimulate or block NO synthesis. Study groups (n=6) had 1) sham laparotomy, 2) ischemia reperfusion (IR), 3) IPC with 5 min ischemia and 10 min reperfusion before IR, 4) l‐arginine before IR, or 5) L‐NAME + IPC before IR. Liver function tests, nitrite + nitrate (NOx) and plasma amino acids were analyzed. The endothelial cell and inducible isoforms of NOS (eNOS and iNOS) were identified using immunohistochemistry and Western blotting. Both IPC and l‐arginine treatment increased NOx (P<0.05) and improved serum liver enzymes (P<0.05) when compared with IR. These effects were prevented by L‐NAME. Hepatic vein NOx was significantly higher than circulating NOx. iNOS expression was absent within the groups. The preconditioned livers were associated with up‐regulation of eNOS expression and also increased l‐arginine levels. The effects of l‐arginine administration were similar to those evident following IPC. Thus, cytoprotective NO generation during IPC of the liver was a result of increased eNOS expression and increased l‐arginine substrate availability.

Continuous infusion of N-acetylcysteine reduces liver warm ischaemia-reperfusion injury.

N‐acetylcysteine (NAC) may modulate the initial phase (less than 2 h) of liver warm ischaemia–reperfusion (IR) injury but its effect on the late phase remains unclear. The present study investigated the role of NAC during the early and late phases in a rabbit lobar IR model.

The Role of Thiols in Liver Ischemia-Reperfusion Injury

Thiol-containing compounds have an essential role in many biochemical reactions due to their ability to be easily oxidised and then quickly regenerated. Main representatives are glutathione, lipoic acid and thioredoxin which are synthesised de novo in mammalian cells. N-acetylcysteine and Bucillamine are synthetic thiols which have been administered in experimental and clinical studies for treatment of conditions associated with oxidative stress. Ischemia and reperfusion (I/R) injury is characterised by significant oxidative stress, characteristic changes in the antioxidant system and organ injury leading to significant morbidity and mortality. I/R occurs in a variety of clinical settings such as liver resection, organ transplantation, haemorrhagic shock with fluid resuscitation, heart surgery, myocardial infarction followed by reperfusion and laparoscopic surgery. In these circumstances, the administration of antioxidant agents such as thiols, could provide protection from the harmful effects of I/R injury. However, the ability of thiol compounds to reduce free radicals is associated with the formation of thiyl radicals and the rate and efficiency of removal of thiyl radicals has a critical effect on antioxidant or prooxidant actions of thiols in the cells. The aim of this review is to present the mechanisms by which thiols act as antioxidants and signalling molecules and the experimental and clinical evidence regarding their role in I/R injury with a particular emphasis on liver I/R. The current evidence suggests that thiols ameliorate I/R injury and that their clinical significance should be further evaluated in large scale randomised clinical trials.

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

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.

Effect of ischaemic preconditioning on hepatic oxygenation, microcirculation and function in a rat model of moderate hepatic steatosis.

IPC (ischaemic preconditioning) may protect the steatotic liver, which is particularly susceptible to I/R (ischaemia/reperfusion) injury. Hepatic steatosis was induced in Sprague-Dawley rats with a high-cholesterol (2%) diet for 12 weeks after which rats were subjected to I/R (ischaemia/reperfusion; 45 min of lobar ischaemia followed by 2 h of reperfusion). Rats were divided into three study groups (n=6 each) receiving: (i) sham laparotomy alone, (ii) I/R, and (iii) IPC (5 min of ischaemia, followed by 10 min of reperfusion) before I/R. Hepatic extra- and intra-cellular oxygenation and HM (hepatic microcirculation) were measured with near-infrared spectroscopy and laser Doppler flowmetry respectively. Plasma liver enzymes and hepatic tissue ATP were measured as markers of liver injury. Histology showed moderate-grade steatosis in the livers. At the end of 2 h of reperfusion, I/R significantly decreased extra- and intra-cellular oxygenation concomitant with a failure of recovery of HM (21.1+/-14.4% of baseline; P<0.001 compared with sham animals). IPC increased intracellular oxygenation (redox state of the copper centre of cytochrome oxidase; P<0.05 compared with rats receiving I/R alone) and flow in HM (70.9+/-17.1% of baseline; P<0.001 compared with rats receiving I/R alone). Hepatocellular injury was significantly reduced with IPC compared with I/R injury alone (alanine aminotransferase, 474.8+/-122.3 compared with 5436.3+/-984.7 units/l respectively; P<0.01; aspartate aminotransferase, 630.8+/-76.9 compared with 3166.3+/-379.6 units/l respectively; P<0.01]. In conclusion, IPC has a hepatoprotective effect against I/R injury in livers with moderate steatosis. These data may have important clinical implications in liver surgery and transplantation.