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Organ Injury (organ + injury)
Selected AbstractsMilk Fat Globule EGF Factor 8 Attenuates Sepsis-Induced Apoptosis and Organ Injury in Alcohol-Intoxicated RatsALCOHOLISM, Issue 9 2010Rongqian Wu Background:, Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. The purpose of this study was to determine whether recombinant murine MFG-E8 (rmMFG-E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis. Methods:, Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10-hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG-E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post-CLP) at a dose of 20 ,g/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements. Results:, Acute alcohol exposure per se did not affect the production of MFG-E8; however, it primed the animal and enhanced sepsis-induced MFG-E8 downregulation in the spleen. Administration of rmMFG-E8 reduces alcohol/sepsis-induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG-E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF-, and interleukin-6 and attenuates organ injury. Conclusions:, rmMFG-E8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. [source] Effect of intravenous lidocaine administration on laminar inflammation in the black walnut extract model of laminitisEQUINE VETERINARY JOURNAL, Issue 3 2010J. M. WILLIAMS Summary Reasons for performing study: Laminitis is a serious complication of horses suffering from sepsis/endotoxaemia-related events. Laminitis in horses and organ injury in human sepsis are both reported to involve inflammatory injury to the laminae/organs including early activation of endothelium and leucocytes leading to emigration of neutrophils into the tissue interstitium. In the black walnut extract (BWE) model, systemic inflammatory events coincide with marked increase in laminar mRNA concentrations of inflammatory genes including proinflammatory cytokines (i.e. IL-1,, IL-6), COX-2, chemokines (i.e. IL-8) and endothelial adhesion molecules (i.e. ICAM-1 and E-selectin). In models of human sepsis, i.v. lidocaine has been reported to decrease leucocyte and endothelial activation, and the expression of proinflammatory cytokines and chemokines. Objectives: To evaluate the effect of i.v. lidocaine therapy on the inflammatory processes documented to occur in the BWE model of laminitis. Methods: Twelve horses were administered BWE and treated immediately with either lidocaine (1.3 mg/kg bwt bolus, followed by 0.05 mg/kg bwt/min CRI, n = 6) or saline (n = 6) for 10 h. At 10 h post BWE administration, laminar samples were obtained under general anaesthesia for assessment of proinflammatory gene expression (using RT-qPCR) and leucocyte emigration (via CD13 immunohistochemistry). At 0, 3 and 10 h post BWE administration, skin samples were obtained for assessment of leucocyte emigration (via calprotectin immunohistochemistry). Results: No significant differences between groups were noted for inflammatory gene mRNA concentrations (IL-1,, IL-6, IL-8, COX-2) or for number of leucocytes present within the laminar interstitium or skin dermis. Increased (P<0.05) laminar E-selectin mRNA concentrations were present in the LD group (vs. SAL group). Conclusions: Continuous administration of i.v. lidocaine does not inhibit inflammatory events in either the laminae or skin in the horse administered black walnut extract. Potential relevance: This work questions the use of continuous i.v. administration of lidocaine as an effective anti-inflammatory therapy for systemic inflammation. [source] The ubiquitin-proteasome system and its role in ethanol-induced disordersADDICTION BIOLOGY, Issue 1 2002Terrence M. Donohue Jr The levels of these proteins are controlled by their rates of degradation. Similarly, protein catabolism plays a crucial role in prolonging cellular life by destroying damaged proteins that are potentially cytotoxic. A major player in these catabolic reactions is the ubiquitin-proteasome system, a novel proteolytic system that has become the primary proteolytic pathway in eukaryotic cells. Ubiquitin-mediated proteolysis is now regarded as the major pathway by which most intracellular proteins are destroyed. Equally important, from a toxicological standpoint, is that the ubiquitin-proteasome system is also widely considered to be a cellular defense mechanism, since it is involved in the removal of damaged proteins generated by adduct formation and oxidative stress. This review describes the history and the components of the ubiquitin-proteasome system, its regulation and its role in pathological states, with the major emphasis on ethanol-induced organ injury. The available literature cited here deals mainly with the effects of ethanol consumption on the ubiquitin-proteasome pathway in the liver. However, since this proteolytic system is an essential pathway in all cells it is an attractive experimental model and therapeutic target in extrahepatic organs such as the brain and heart that are also affected by excessive alcohol consumption. [source] Effects of melatonin and caffeic acid phenethyl ester on testicular injury induced by myocardial ischemia/reperfusion in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2005Mukaddes E Abstract Experimental studies indicate that ischemia/reperfusion (I/R) causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative injury on testicular damage following myocardial I/R injury and the effects of antioxidant agents, melatonin and caffeic acid phenethyl ester (CAPE), on testicular injury were investigated. As far as we know, this is the first report demonstrating that myocardial I/R induces damage to the testes. Thirty-two male Wistar rats were randomly divided into four groups: sham operation (SO), I/R + vehicle, I/R + melatonin, and I/R + caffeic acid phenethyl ester. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Serum nitric oxide (NO) and malondialdehyde (MDA) levels and morphological changes were examined. I/R was accompanied by a significant increase in serum MDA and NO levels, whereas, melatonin and CAPE administration significantly reduced these values. Melatonin was more efficient in reducing MDA levels than CAPE (P < 0.05). I/R induced myocardial damage, manifested as the histopathological evidence of intracellular vacuolization, interstitial edema, neutrophil infiltration and coagulative necrosis. I/R + vehicle group showed many histological alterations such as focal tubular atrophy, and degeneration and disorganization of the seminiferous epithelium in testes. The number of atrophic tubules and degenerating cells was significantly higher in I/R + vehicle group than that of SO group. Melatonin and CAPE significantly reduced the number of degenerating cells; additionally, melatonin reduced the number of atrophic tubules (P < 0.05). Our results indicate that myocardial I/R induces severe testicular damage and antioxidant agents, especially melatonin, have protective effects on testicular injury after myocardial I/R. Our data emphasize that oxygen-based reactants may play a central role in remote organ injury. [source] Gene delivery of Cu/Zn-superoxide dismutase improves graft function after transplantation of fatty livers in the ratHEPATOLOGY, Issue 6 2000Thorsten G. Lehmann Oxygen-derived free radicals play a central role in reperfusion injury after organ transplantation, and fatty livers are particularly susceptible. Endogenous radical scavengers such as superoxide dismutase (SOD) degrade these radicals; however, SOD is destroyed rapidly when given exogenously. Therefore, an adenoviral vector encoding the Cu/Zn-SOD gene (Ad.SOD1) was used here to test the hypothesis that organ injury would be reduced and survival increased in a rat model of transplantation of fatty livers. Donors received chow diet (untreated), high-fat diet, or ethanol-containing high-fat diet. Some of the ethanol-fed donors were infected either with the gene lacZ encoding bacterial ,-galactosidase (Ad.lacZ), or Ad.SOD1. After liver transplantation, SOD activity and protein expression in liver, survival, histopathology, release of transaminases, free radical adducts in bile, and activation of NF-,B, I,B kinase (IKK), Jun-N-terminal kinase (JNK), and TNF, were evaluated. Ad.SOD1 treatment increased survival dramatically, blunted transaminase release, and reduced necrosis and apoptosis significantly. Free radical adducts were increased two-fold in the ethanol group compared with untreated controls. Ad.SOD1 blunted this increase and reduced the activation of NF-,B. However, release of TNF, was not affected. Ad.SOD1 also blunted JNK activity after transplantation. This study shows that gene therapy with Ad.SOD1 protects marginal livers from failure after transplantation because of decreased oxygen radical production. Genetic modification of fatty livers using viral vectors represents a new approach to protect marginal grafts against primary nonfunction. [source] Epidemiology of major paediatric chest traumaJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 11 2009Sumudu P Samarasekera Aim: Paediatric chest trauma is a marker of severe injury and a significant cause of morbidity and mortality. However, current trends in the Australian population are unknown. This study aims to outline the profile and management of major paediatric chest trauma in Victoria. Methods: Prospectively collected data of patients from the Victorian State Trauma Registry from July 2001 to June 2007 were retrospectively reviewed. Data on fatalities were obtained from the National Coroners Information System. Descriptive statistics were used to summarise the profiles of major trauma cases and coroners' cases. Results: Overall, 204 cases with serious paediatric chest injuries were reported by the Victorian State Trauma Registry (n = 158) and National Coroners Information System (n = 46) (excluding overlapping cases) in 2001,2007. Paediatric chest trauma was more common in males. The Injury Severity Score ranged from 16 to 25 in most patients. Blunt trauma was responsible for 96% of cases, of which motor vehicle collisions accounted for 75%. Median hospitalisation was 9 days, and 64% of patients were admitted to intensive care. Common injuries included lung contusion (66%), haemo/pneumothorax (32%) and rib fracture (23%). Multiple organ injury occurred in 99% of cases, with head (62%) and abdominal (50%) injury common. Management was conservative, with only 11 cases (7%) treated surgically. The highest mortality was in the 10,15-year age group. In 52 (79%) fatalities, injury was transport related. Conclusion: Australian paediatric chest trauma trends are similar to international patterns. Serious injury requiring surgical intervention is rare. This limited exposure may lead to difficulty in maintaining surgical expertise in this highly specialised area. [source] Milk Fat Globule EGF Factor 8 Attenuates Sepsis-Induced Apoptosis and Organ Injury in Alcohol-Intoxicated RatsALCOHOLISM, Issue 9 2010Rongqian Wu Background:, Despite advances in our understanding of excessive alcohol-intake-related tissue injury and modernization of the management of septic patients, high morbidity and mortality caused by infectious diseases in alcohol abusers remain a prominent challenge. Our previous studies have shown that milk fat globule epidermal growth factor-factor VIII (MFG-E8), a protein required to opsonize apoptotic cells for phagocytosis, is protective in inflammation. However, it remains unknown whether MFG-E8 ameliorates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. The purpose of this study was to determine whether recombinant murine MFG-E8 (rmMFG-E8) attenuates organ injury after acute alcohol exposure and subsequent sepsis. Methods:, Acute alcohol intoxication was induced in male adult rats by a bolus injection of intravenous alcohol at 1.75 g/kg BW, followed by an intravenous infusion of 300 mg/kg BW/h of alcohol for 10 hours. Sepsis was induced at the end of 10-hour alcohol infusion by cecal ligation and puncture (CLP). rmMFG-E8 or vehicle (normal saline) was administered intravenously 3 times (i.e., at the beginning of alcohol injection, the beginning of CLP, and 10 hours post-CLP) at a dose of 20 ,g/kg BW each. Blood and tissue samples were collected 20 hours after CLP in alcoholic animals for various measurements. Results:, Acute alcohol exposure per se did not affect the production of MFG-E8; however, it primed the animal and enhanced sepsis-induced MFG-E8 downregulation in the spleen. Administration of rmMFG-E8 reduces alcohol/sepsis-induced apoptosis in the spleen, lungs, and liver. In addition, administration of rmMFG-E8 after alcohol exposure and subsequent sepsis decreases circulating levels of TNF-, and interleukin-6 and attenuates organ injury. Conclusions:, rmMFG-E8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. [source] Melatonin protects against endosulfan-induced oxidative tissue damage in ratsJOURNAL OF PINEAL RESEARCH, Issue 4 2008Gülden Z. Omurtag Abstract:, Endosulfan is a chlorinated cyclodiene insecticide which induces oxidative stress. In this study, we investigated the possible protective effect of melatonin, an antioxidant agent, against endosulfan (Endo)-induced toxicity in rats. Wistar albino rats (n = 8) were administered endosulfan (22 mg/kg/day orally) followed by either saline (Endo group) or melatonin (10 mg/kg/day, Endo + Mel group) for 5 days. In other rats, saline (control group) or melatonin (10 mg/kg/day, Mel group) was injected for 5 days, following corn oil administration (vehicle of endosulfan). Measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were performed in liver and kidney. Furthermore, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels, lactate dehydrogenase (LDH) activity were measured in the serum samples, while tumor necrosis factor-, (TNF-,), interleukin-, (IL-,) and total antioxidant capacity (AOC) were assayed in plasma samples. Endosulfan administration caused a significant decrease in tissue GSH and plasma AOC, which was accompanied with significant rises in tissue MDA and collagen levels and MPO activity. Moreover, the proinflammatory mediators (TNF-, and IL-,), LDH activity, AST, ALT, creatinine and BUN levels were significantly elevated in the endosulfan-treated rats. On the other hand, melatonin treatment reversed all these biochemical alterations induced by endosulfan. Our results suggest that oxidative mechanisms play an important role in endosulfan-induced tissue damage and melatonin, by inhibiting neutrophil infiltration, balancing oxidant,antioxidant status and regulating the generation of inflammatory mediators, ameliorates oxidative organ injury as a result of endosulfan toxicity. [source] Melatonin ameliorates chronic renal failure-induced oxidative organ damage in ratsJOURNAL OF PINEAL RESEARCH, Issue 4 2004Göksel, ener Abstract:, Chronic renal failure (CRF) is associated with oxidative stress that promotes production of reactive oxygen species (ROS). Melatonin, the chief secretory product of the pineal gland, was recently found to be a potent free radical scavenger and antioxidant. The aim of this study was to examine the role of melatonin in protecting the aorta, heart, corpus cavernosum, lung, diaphragm, and kidney tissues against oxidative damage in a rat model of CRF, which was induced by five of six nephrectomy. Male Wistar albino rats were randomly assigned to either the CRF group or the sham-operated control group, which had received saline or melatonin (10 mg/kg, i.p.) for 4 wk. CRF was evaluated by serum blood urea nitrogen (BUN) level and creatinine measurements. Aorta and corporeal tissues were used for contractility studies, or stored along with heart, lung, diaphragm, and kidney tissues for the measurement of malondialdehyde (MDA, an index of lipid peroxidation), protein carbonylation (PC, an index for protein oxidation), and glutathione (GSH) levels (a key antioxidant). Plasma MDA, PC, and GSH levels and erythrocytic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were studied to evaluate the changes of antioxidant status in CRF. In the CRF group, the contraction and the relaxation of aorta and corpus cavernosum samples decreased significantly compared with controls (P < 0.05,0.001). Melatonin treatment of the CRF group restored these responses. In the CRF group, there were significant increases in tissue MDA and PC levels in all tissues with marked reductions in GSH levels compared with controls (P < 0.05,0.001). In the plasma, while MDA and PC levels increased, GSH, SOD, CAT, and GSH-Px activities were reduced. Melatonin treatment reversed these effects as well. In this study, the increase in MDA and PC levels and the concomitant decrease in GSH levels of tissues and plasma and also SOD, CAT, GSH-Px activities of plasma demonstrate the role of oxidative mechanisms in CRF-induced tissue damage, and melatonin, via its free radical scavenging and antioxidant properties, ameliorates oxidative organ injury. CRF-induced dysfunction of the aorta and corpus cavernosum of rats was reversed by melatonin treatment. Thus, supplementing CRF patients with adjuvant therapy of melatonin may have some benefit. [source] Hemorrhagic bile pleuritis and peritonitis secondary to traumatic common bile duct rupture, diaphragmatic tear, and rupture of the spleen in a dogJOURNAL OF VETERINARY EMERGENCY AND CRITICAL CARE, Issue 6 2008Gordon D. Peddle VMD Abstract Objective, To describe the diagnosis and successful treatment of bile pleuritis and peritonitis secondary to traumatic rupture of the common bile duct and a diaphragmatic tear in a young dog. Case Summary, A 1-year-old German Shepherd dog was referred for evaluation of vomiting and icterus 4 days after being hit by a car. Thoracic radiographs, thoracic and abdominal ultrasonographic examinations, thoraco- and abdominocentesis, and positive contrast celiogram indicated hemorrhagic pleuritis and peritonitis, left dorsal diaphragmatic tear, and rupture and infarct of the spleen. Surgical exploration of the abdomen confirmed these findings in addition to a circumferential tear of the common bile duct, leading to a diagnosis of hemorrhagic bile pleuritis and peritonitis. Aerobic and anaerobic bacterial culture of the abdominal fluid yielded no growth. Surgical correction of the traumatic injuries was achieved via common bile duct anastomosis, cholecystojejunostomy, repair of the diaphragm, and splenectomy. The dog developed postoperative signs consistent with aspiration pneumonia but was successfully treated and discharged from the hospital. Clinical signs and laboratory abnormalities resolved and the dog was alive and healthy 8 months after discharge. New or Unique Information Provided, Bile pleuritis is rare in dogs and cats and is usually associated with penetrating, not blunt, abdominal trauma. Multiple organ injury in cases of traumatic bile duct rupture is uncommon; in this dog, rupture of the common bile duct was accompanied by rupture of the diaphragm and spleen. [source] Microvascular Display of Xanthine Oxidase and NADPH Oxidase in the Spontaneously Hypertensive RatMICROCIRCULATION, Issue 7 2006FRANK A. DELANO ABSTRACT Objective: Oxygen free radical production in hypertension may be associated with elevated arteriolar tone and organ injury. Previous results suggest an enhanced level of oxygen free radical formation in microvascular endothelium and in circulating neutrophils associated with xanthine oxidase activity in the spontaneously hypertensive rats (SHR) compared with their normotensive controls, the Wistar Kyoto rats (WKY). The aim of this study was to gain more detailed understanding of where oxidative enzymes are located in the microcirculation. Methods: An approach was developed to delineate the cellular distribution of two selected oxidative enzymes, xanthine oxidase and nicotinamide adenine dinucleotide phosphate (NADPH) dependent oxidase (protein 67-kDa fraction). Immunolabeling with peroxidase substrate was utilized, which permits full delineation of the primary antibody in all microvascular structures of the mesentery. Results: Xanthine oxidase is present in the endothelium of all segments of the microcirculation, in mast cells, and in parenchymal cells of the mesentery. NADPH oxidase can be detected in the endothelium, leukocytes, and mast cells and with lower levels in parenchymal cells. The mesentery of WKY and SHR has similar enzyme distributions with enhancements on the arteriolar and venular side of the microcirculation that coincide with the sites of enhanced free radical production recently reported. Immune label measurements under standardized conditions indicate that both enzymes are significantly enhanced in the SHR. Adrenalectomy, which serves to reduce the blood pressure and free radical production of the SHR to normotensive levels, leads to a reduction of NADPH and xanthine oxidase to normotensive levels, while supplementation of adrenalectomized SHR with dexamethasone significantly increases the oxidase expression in several parts of the microcirculation to levels above the WKY rats. Conclusion: The results indicate that enhanced expression of NADPH and xanthine oxidase in the SHR depends on an adrenal pathway that is detectable in the arteriolar and venular network at high and low pressure regions of the circulation. [source] High-density lipoprotein prevents organ damage in endotoxemia,RESEARCH IN NURSING & HEALTH, Issue 3 2007Ru-Ping Lee Abstract High-density lipoprotein (HDL) may decrease organ injury in sepsis. This study was designed using an animal model to mimic people who had a high HDL level and to test HDL effects on preventing organ damage in endotoxemia. Endotoxemia was induced by an infusion of lipopolysac-charide (LPS) after HDL or LDL administration. Levels of blood biochemical substances, nitrate/nitrite, and TNF-, in sera were measured. Pathological examinations were performed 72 hours after LPS infusion. HDL decreased the endotoxin-induced elevation of AST, ALT, BUN, creatinine, LDH, CPK, nitrate/nitrite, and TNF-,. On histological examination, neutrophil infiltration was lower in the HDL group. HDL had a significant effect in preventing endotoxin-induced organ damage. © 2007 Wiley Periodicals, Inc. Res Nurs Health 30: 250,260, 2007 [source] Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor ,,THE JOURNAL OF PATHOLOGY, Issue 4 2007F Fortunato Abstract Alcohol exposure is known to sensitize acinar cells to various insults but the pathophysiological mechanisms of alcoholic pancreatitis remain unknown. Alcohol abuse has been shown to mediate an anti-inflammatory response and periods of immune suppression seem to be associated with organ injury and mortality. The purpose of this study was to determine the mechanisms by which alcohol exerts transcriptional activities in the rat pancreas and how alcohol alters the inflammatory response. Using the Lieber,DeCarli alcohol/control diet, rats that were fed with alcohol over 14 weeks demonstrated a decrease of inflammatory cells in pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNF,, IL-1,, IL-18, TGF,, and MCP-1. In addition, alcohol significantly increased the activity of PPAR,, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NF,B binding showed a tendency towards a reduction. Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied by peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the pancreas exposed to alcohol maintains an anti-inflammatory state by activating PPAR,. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Alloimmune Activation Enhances Innate Tissue Inflammation/Injury in a Mouse Model of Liver Ischemia/Reperfusion InjuryAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010X. Shen The deleterious sensitization to donor MHC Ags represents one of the most challenging problems in clinical organ transplantation. Although the role of effector/memory T cells in the rejection cascade has been extensively studied, it remains unknown whether and how these ,Ag-specific' cells influence host innate immunity, such as tissue inflammation associated with ischemia and reperfusion injury (IRI). In this study, we analyzed how allogeneic skin transplant (Tx) affected the sequel of host's own liver damage induced by partial warm ischemia and reperfusion. Our data clearly showed that allo-Tx recipients had increased inflammatory response against IR insult in their native livers, as evidenced by significantly more severe hepatocelluar damage, compared with syngeneic Tx recipient controls, and determined by serum ALT levels, liver histology (Suzuki's score) and intrahepatic proinflammatory gene inductions (TNF-,, IL-1, and CXCL10). The CD4 T cells, but neither CD8 nor NK cells, mediated the detrimental effect of allo-Ag sensitization in liver IRI. Furthermore, CD154, but not IFN-,, was the key mechanism in allo-Tx recipients to facilitate IR-triggered liver damage. These results provide new evidence that alloreactive CD4 T cells are capable of enhancing innate tissue inflammation and organ injury via an Ag-nonspecific CD154-dependent but IFN-, independent mechanism. [source] Donor Intervention and Organ Preservation: Where Is the Science and What Are the Obstacles?AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010S. Feng The organ shortage is widely acknowledged as the most critical factor hindering the full realization of success for solid organ transplantation. Innovation in the areas of donor management and organ preservation offers the most realistic hope to improve both the quality and size of the current organ supply. Although the basic science dissecting the complex processes of brain death and ischemia/reperfusion injury is replete with exciting discoveries, the clinical science investigating donor management and organ preservation is sparse in contrast. This review will survey the current landscape of trials to mitigate organ injury through interventions administered to donors in vivo or organs ex vivo. Consideration will then be given to the scientific, logistical and ethical obstacles that impede the transformation of laboratory breakthroughs into innovative treatments that simultaneously improve organ quality and supply. [source] Signal Transduction Pathways Involved in Brain Death-Induced Renal InjuryAMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2009H. R. Bouma Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to endothelial dysfunction and the release of cytokines in the circulation. Serum levels of interleukin-6, -8, -10, and monocyte chemoattractant protein-1 (MCP-1) are increased after brain death. Binding with cytokine-receptors in kidneys stimulates activation of nuclear factor-kappa B (NF-,B), selectins, adhesion molecules and production of chemokines leading to cellular influx. Mitogen-activated protein kinases (MAP-kinases) mediate inflammatory responses and together with NF-,B they seem to play an important role in brain death induced renal injury. Altering the activation state of MAP-kinases could be a promising drug target for early intervention to reduce cerebral injury related donor kidney damage and improve outcome after transplantation. [source] Beating-Heart Coronary Artery Bypass Grafting With Miniaturized Cardiopulmonary Bypass Results in a More Complete Revascularization When Compared to Off-Pump GraftingARTIFICIAL ORGANS, Issue 3 2010Delawer Reber Abstract The technique of miniaturized cardiopulmonary bypass (M-CPB) for beating-heart coronary artery bypass grafting (CABG) is relatively new and has potential advantages when compared to conventional cardiopulmonary bypass (CPB). M-CPB consists of less tubing length and requires less priming volume. The system is phosphorylcholine coated and results in minimal pump-related inflammatory response and organ injury. Finally, this technique combines the advantages of the off-pump CABG (OPCAB) with the better exposure provided by CPB to facilitate complete revascularization. The hypothesis is that CABG with M-CPB has a better outcome in terms of complete coronary revascularization and perioperative results as that compared to off-pump CABG (OPCAB). In a retrospective study, 302 patients underwent beating-heart CABG, 117 (39%) of them with the use of M-CPB and 185 (61%) with OPCAB. After propensity score matching 62 patients in both groups were demographically similar. The most important intra- and early-postoperative parameters were analyzed. Endpoints were hospital mortality and complete revascularization. Hospital mortality was comparable between the groups. The revascularization was significantly more complete in M-CPB patients than in patients in the OPCAB group. Beating-heart CABG with M-CPB is a safe procedure and it provides an optimal operative exposure with significantly more complete coronary revascularization when compared to OPCAB. Beating-heart CABG with the support of a M-CPB is the operation of choice when total coronary revascularization is needed. [source] Control of Oxidative Reactions of Hemoglobin in the Design of Blood Substitutes: Role of the Ascorbate,Glutathione Antioxidant SystemARTIFICIAL ORGANS, Issue 2 2009Jan Simoni Abstract Uncontrolled oxidative reactions of hemoglobin (Hb) are still the main unresolved problem for Hb-based blood substitute developers. Spontaneous oxidation of acellular ferrous Hb into a nonfunctional ferric Hb generates superoxide anion. Hydrogen peroxide, formed after superoxide anion dismutation, may react with ferrous/ferric Hb to produce toxic ferryl Hb, fluorescent heme degradation products, and/or protein-based free radicals. In the presence of free iron released from heme, superoxide anion and hydrogen peroxide might react via the Haber,Weiss and Fenton reactions to generate the hydroxyl radical. These highly reactive oxygen and heme species may not only be involved in shifting the cellular redox balance to the oxidized state that facilitates signal transduction and pro-inflammatory gene expression, but could also be involved in cellular and organ injury, and generation of vasoactive compounds such as isoprostanes and angiotensins. It is believed that these toxic species may be formed after administration of Hb-based blood substitutes, particularly in ischemic patients with a diminished ability to control oxidative reactions. Although varieties of antioxidant strategies have been suggested, this in vitro study examined the ability of the ascorbate,glutathione antioxidant system in preventing Hb oxidation and formation of its ferryl intermediate. The results suggest that although ascorbate is effective in reducing the formation of ferryl Hb, glutathione protects heme against excessive oxidation. Ascorbate without glutathione failed to protect the red blood cell membranes against Hb/hydrogen peroxide-mediated peroxidation. This study provides evidence that the ascorbate,glutathione antioxidant system is essential in attenuation of the pro-oxidant potential of redox active acellular Hbs, and superior to either ascorbate or glutathione alone. [source] Comparative Effectiveness of Methylprednisolone and Zero-balance Ultrafiltration on Inflammatory Response After Pediatric Cardiopulmonary BypassARTIFICIAL ORGANS, Issue 7 2007Jinping Liu Abstract:, Studies have demonstrated that systemic inflammatory response syndrome (SIRS) remains one of the major causes of cardiopulmonary bypass (CPB)-associated organ injury during pediatric cardiac surgery. The purpose of this investigation was to compare the effectiveness of methylprednisolone (MP) and zero-balance ultrafiltration (ZBUF) on SIRS during pediatric CPB. Thirty infants undergoing open-heart surgeries were randomized to receive either MP in the priming solution (group M, n = 15) or ZBUF during CPB (group Z, n = 15). All the patients survived. Plasma levels of tumor necrosis factor-, (TNF-,), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) were measured before CPB (T1), 5 min after the start of CPB (T2), at the termination of CPB (T3), the fourth hour (T4), and the eighth hour (T5) postoperatively. The results showed that the plasma concentrations of TNF-, in the Z group were significantly less than those in the M group at T4 and T5 (P < 0.05), and the plasma concentrations of IL-6 were significantly less than those in the M group at T4 (P < 0.05); the plasma concentrations of IL-8 in the Z group were significantly less than those in the M group at T5 (P < 0.05). There was no difference between two groups on the plasma concentrations of IL-10. The duration of postoperative mechanical ventilation was (9.6 ± 0.8 h) in the M group and (7.8 ± 0.4 h) in the Z group (P < 0.05). This study showed that application of ZBUF is more effective to decrease the level of inflammatory mediators including TNF-,, IL-6, and IL-8 than administration of MP after pediatric CPB. [source] Intestinal-FABP and Liver-FABP: Novel Markers for Severe Abdominal InjuryACADEMIC EMERGENCY MEDICINE, Issue 7 2010Borna Relja MSc ACADEMIC EMERGENCY MEDICINE 2010; 17:729,735 © 2010 by the Society for Academic Emergency Medicine Abstract Objectives:, Fatty acid,binding proteins (FABPs) have relatively high tissue concentrations and low plasma concentrations and are released into the circulation following organ injury. We explored the utility of intestinal-(I)-FABP and liver-(L)-FABP for the diagnosis of abdominal injury in patients with multiple trauma. Methods:, This prospective study included 102 trauma patients and 30 healthy volunteers. Plasma I-FABP and L-FABP levels were measured in the emergency department (ED) by enzyme-linked immunosorbent assay (ELISA). Forty-one patients suffered from serious or severe abdominal trauma (Abbreviated Injury Score [AIS] code "ai" for abdominal injury, AISai , 3) and nine were moderately abdominally injured (AISai < 3). Fifty-two had no abdominal injury. Results:, Median I-FABP and L-FABP levels in the AISai , 3 group (516 pg/mL and 135 ng/mL, respectively) were significantly higher compared to the AISai < 3 group (154 pg/mL and 13 ng/mL, respectively) or those without abdominal injury (207 pg/mL and 21 ng/mL, respectively) or normal controls (108 pg/mL and 13 ng/mL, respectively). The cutoff to distinguish the ai , 3 is 359 pg/mL for I-FABP and 54 ng/mL for L-FABP, with 93% specificity and 75% sensitivity for I-FABP and 93% and 82% for L-FABP, respectively. Conclusions:, High I-FABP and L-FABP levels correlate with relevant severity of abdominal tissue damage in patients with multiple trauma. I-FABP and L-FABP could be useful as markers for the early detection of significant abdominal injury in acute multiple trauma and identify patients who require rapid intervention. [source] Is Hospital Admission and Observation Required after a Normal Abdominal Computed Tomography Scan in Children with Blunt Abdominal Trauma?ACADEMIC EMERGENCY MEDICINE, Issue 10 2008Smita Awasthi MD Abstract Objectives:, The objective was to determine if hospital admission of children with blunt abdominal trauma for observation of possible intraabdominal injury (IAI) is necessary after a normal abdominal computed tomography (CT) scan in the emergency department (ED). Methods:, The authors conducted a prospective observational cohort study of children less than 18 years of age with blunt abdominal trauma who underwent an abdominal CT scan in the ED. Abdominal CT scans were obtained with intravenous contrast but no oral contrast. The decision to hospitalize the patient was made by the attending emergency physician (EP) with the trauma or pediatric surgery teams. An abnormal abdominal CT scan was defined by the presence of any visualized IAI or findings suggestive of possible IAI (e.g., intraperitoneal fluid without solid organ injury). Patients were followed to determine if IAI was later diagnosed and the need for acute therapeutic intervention if IAI was present. Results:, A total of 1,295 patients underwent abdominal CT, and 1,085 (84%) patients had normal abdominal CT scans in the ED and make up the study population. Seven-hundred thirty-seven (68%) were hospitalized, and 348 were discharged to home. None of the 348 patients discharged home and 2 of the 737 hospitalized patients were identified with an IAI after a normal initial abdominal CT. The IAIs in patients with normal initial CT scans included a 10-year-old with a mesenteric hematoma and serosal tear at laparotomy and a 10-year-old with a perinephric hematoma on repeat CT. Neither underwent specific therapy. The negative predictive value (NPV) of a normal abdominal CT scan for IAI was 99.8% (95% confidence interval [CI] = 99.3% to 100%). Conclusions:, Children with blunt abdominal trauma and a normal abdominal CT scan in the ED are at very low risk of having a subsequently diagnosed IAI and are very unlikely to require a therapeutic intervention. Hospitalization of children for evaluation of possible undiagnosed IAI after a normal abdominal CT scan has a low yield and is generally unnecessary. [source] Causes of death in sickle cell disease: an autopsy studyBRITISH JOURNAL OF HAEMATOLOGY, Issue 2 2003Elizabeth A. Manci Summary. More precise analysis of causes of death is needed to focus research efforts and improve morbidity and mortality in sickle cell disease. In this study, the morphological evidence of the cause of death was studied in 306 autopsies of sickle cell disease, which were accrued between 1929 and 1996. The most common cause of death for all sickle variants and for all age groups was infection (33,48%). The terminal infection was heralded by upper respiratory tract syndromes in 72·6% and by gastroenteritis in 13·7%. The most frequent portal of entry in children was the respiratory tract but, in adults, a site of severe chronic organ injury. Other causes of death included stroke 9·8%, therapy complications 7·0%, splenic sequestration 6·6%, pulmonary emboli/thrombi 4·9%, renal failure 4·1%, pulmonary hypertension 2·9%, hepatic failure 0·8%, massive haemolysis/red cell aplasia 0·4% and left ventricular failure 0·4%. Death was frequently sudden and unexpected (40·8%) or occurred within 24 h after presentation (28·4%), and was usually associated with acute events (63·3%). This study shows that the first 24 h after presentation for medical care is an especially perilous time for patients with sickle cell disease and an acute event. Close monitoring and prompt aggressive treatment are warranted. [source] Protective mechanisms of activated protein C in severe inflammatory disordersBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2009Arne P Neyrinck The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure,function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 [source] Preclinical Studies with Adrenomedullin and Its Binding Protein as Cardiovascular Protective Agents for Hemorrhagic ShockCARDIOVASCULAR THERAPEUTICS, Issue 3-4 2006Rongqian Wu ABSTRACT Traumatic injury is a major, largely unrecognized public health problem in the US that cuts across race, gender, age, and economic boundaries. The resulting loss of productive life years exceeds that of any other disease, with societal costs of $469 billion annually. Most trauma deaths result either from insufficient tissue perfusion due to excessive blood loss, or the development of inflammation, infection, and vital organ damage following resuscitation. Clinical management of hemorrhagic shock relies on massive and rapid infusion of fluids to maintain blood pressure. However, the majority of victims with severe blood loss do not respond well to fluid restoration. The development of effective strategies for resuscitation of traumatic blood loss is therefore critically needed. We have recently discovered that the vascular responsiveness to a recently-discovered potent vasodilatory peptide, adrenomedullin (AM) is depressed after severe blood loss, which may be due to downregulation of a novel specific binding protein, AM binding protein-1 (AMBP-1). Using three different animal models of hemorrhage (controlled hemorrhage with large volume resuscitation, controlled hemorrhage with low volume resuscitation, and uncontrolled hemorrhage with minimum resuscitation), we have shown that cell and organ injury occurs after hemorrhage despite fluid resuscitation. Administration of AM/AMBP-1 significantly improves cardiac output, heart performance and tissue perfusion, attenuates hepatic and renal injury, decreases pro-inflammatory cytokines, prevents metabolic acidosis, and reduces hemorrhage-induced mortality. Thus, administration of AM/AMBP-1 appears to be a novel and useful approach for restoring cardiovascular responses, preventing organ injury, and reducing mortality after hemorrhagic shock. [source] Rationale and timeliness for IL-1,-targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantationCLINICAL TRANSPLANTATION, Issue 3 2010Alan A. Wanderer Wanderer AA. Rationale and timeliness for IL-1,-targeted therapy to reduce allogeneic organ injury at procurement and to diminish risk of rejection after transplantation. Clin Transplant 2010: 24: 307,311. © 2010 John Wiley & Sons A/S. Abstract:, Ischemia-reperfusion injury (IRI) involving allograft transplantation and procured organs may in part be induced by stimulation of a newly described innate pro-inflammatory immune system (i.e., NALP-3-inflammasome), which can cause secretion of IL-1, and subsequent neutrophilic inflammation. Ischemia and/or hypoxia/anoxia can induce anaerobic metabolism with metabolic acidosis and subsequent development of danger signals known to stimulate IL-1, secretion from the NALP-3 inflammasome. Observations from IRI studies and hereditary auto-inflammatory syndromes with NALP-3 inflammasome mutations suggest that IL-1, secretion can induce robust neutrophilic inflammation that is responsive to IL-1, targeted therapy. Based on these observations and data from transplantation studies, it may be timely to consider commercially available IL-1, targeted biologic therapy to improve allograft tolerance and viability of procured organs. [source] | ||||||||||||||||||||||||||||