Blue light reduces organ injury from ischemia and reperfusion.
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ABSTRACT:
SUBMITTER: Yuan D
PROVIDER: S-EPMC4868436 | biostudies-other | 2016 May
REPOSITORIES: biostudies-other
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Project description:OBJECTIVES:The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. DESIGN:Laboratory animal research, pilot human feasibility trial. SETTING:University basic science laboratory and tertiary care hospital. SUBJECTS:Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. INTERVENTIONS:Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. MEASUREMENTS AND MAIN RESULTS:Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERB? and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. CONCLUSIONS:Modifying the spectrum of light may offer therapeutic utility in sepsis.
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Project description:Intestinal ischemia/reperfusion (I/R) injury occurs during transplantation, mesenteric arterial occlusion, trauma and shock, causing systemic inflammation, multiple organ dysfunction and high mortality. Pancreatic secretory trypsin inhibitor (PSTI), a serine protease inhibitor expressed in gut mucosa may function as a mucosal protective/repair peptide. We examined whether PSTI affected mesenteric I/R-induced injury. Hypoxia/normoxia (H/N) caused 50% drop in cell viability of AGS, RIE1 and Caco-2 cells but PSTI (10 ?g/ml) given prior- or during-hypoxic period improved survival by 50% (p<0.01). Similarly, Caco-2 monolayers exposed to H/N had 300% increase in transepithelial permeability, PSTI truncated this by 50% (p<0.01). Mice underwent mesenteric I/R by clamping jejunum, causing severe mucosal injury, increased apoptotic markers and 3-fold increases in plasma IL-6, IL1?, TNF?, and tissue lipid peroxidation (MDA) and inflammatory infiltration (MPO) levels. Lungs showed similar significant injury and inflammatory infiltrate markers. Smaller increases in MDA and MPO were seen in kidney & liver. PSTI (20 mg/kg) reduced all injury markers by 50-80% (p<0.01). In vitro and in vivo studies showed PSTI reduced pro-apoptotic Caspase 3, 9 and Bax? levels, normalised Bcl2 and caused additional increases in HIF1?, VEGF and Hsp70 above rises caused by I/R alone (all p<0.01). PSTI also prevented reduction of tight junction molecules ZO1 and Claudin1 (all p<0.01) but did not affect increased ICAM-1 caused by I/R in gut or lung. PSTI may be a useful clinical target to prevent I/R injury.
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Project description:The shortage of donor organs is a major global concern. Organ failure requires the transplantation of functional organs. Donor's organs are preserved for variable periods of warm and cold ischemia time, which requires placing them into a preservation device. Ischemia and reperfusion damage the organs, due to the lack of oxygen during the ischemia step, as well as the oxidative stress during the reperfusion step. Different methodologies are developed to prevent or to diminish the level of injuries. Preservation solutions were first developed to maximize cold static preservation, which includes the addition of several chemical compounds. The next chapter of organ preservation comes with the perfusion machine, where mechanical devices provide continuous flow and oxygenation ex vivo to the organs being preserved. In the addition of inhibitors of mitogen-activated protein kinase and inhibitors of the proteasome, mesenchymal stem cells began being used 13 years ago to prevent or diminish the organ's injuries. Mesenchymal stem cells (e.g., bone marrow stem cells, adipose derived stem cells and umbilical cord stem cells) have proven to be powerful tools in repairing damaged organs. This review will focus upon the use of some bone marrow stem cells, adipose-derived stem cells and umbilical cord stem cells on preventing or decreasing the injuries due to ischemia-reperfusion.
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Project description:High mobility group box1 (HMGB1) promotes inflammatory injury, and accumulating evidence suggests that it plays a key role in brain ischemia reperfusion (I/R), as well as the development of diabetes mellitus (DM). The purpose of this study was to investigate whether HMGB1 plays a role in brain I/R in a DM mouse model. Diabetes mellitus was induced by a high-calorie diet and streptozotocin treatment, and cerebral ischemia was induced by middle cerebral artery occlusion. We examined HMGB1 levels following cerebral I/R injury in DM and non-DM mice and evaluated the influence of altered HMGB1 levels on the severity of cerebral injury. Serum HMGB1 levels and the inflammatory factors IL-1?, IL-6, and inflammation-related enzyme iNOS were significantly elevated in DM mice with brain I/R compared with non-DM mice with brain I/R. Blocking HMGB1 function by intraperitoneal injection of anti-HMGB1 neutralizing antibodies reversed the inflammatory response and the extent of brain damage, suggesting that HMGB1 plays an important role in cerebral ischemic stroke in diabetic mice.
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Project description:Limitation of infarct size is a major goal of therapy for acute coronary syndromes, and research has focused on achieving rapid patency of infarct-related vessels. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches that have not been extensively explored. Here, we show that ischemia induces histone deacetylase (HDAC) activity in the heart with deacetylation of histones H3/4 in vitro and in vivo. We show, utilizing a standard murine model of ischemia-reperfusion, that chemical HDAC inhibitors significantly reduce infarct area, even when delivered 1 h after the ischemic insult. We demonstrate that HDAC inhibitors prevent ischemia-induced activation of gene programs that include hypoxia inducible factor-1alpha, cell death, and vascular permeability in vivo and in vitro, thus providing potential mechanisms to explain reduced vascular leak and myocardial injury. In vitro, siRNA knockdown experiments implicate HDAC4 as a mediator of the effects in ischemic cardiac myocytes. These results demonstrate that HDAC inhibitors alter the response to ischemic injury in the heart and reduce infarct size, suggesting novel therapeutic approaches for acute coronary syndromes.
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Project description:Post-ischemic neurodegeneration remains the principal cause of mortality following cardiac resuscitation. Recent studies have implicated gastrointestinal ischemia in the sepsis-like response associated with the post-cardiac arrest syndrome (PCAS). However, the extent to which the resulting low-grade endotoxemia present in up to 86% of resuscitated patients affects cerebral ischemia-reperfusion injury has not been investigated. Here we report that a single injection of low-dose lipopolysaccharide (50?g/kg, IP) delivered after global cerebral ischemia (GCI) induces blood-brain barrier permeability, microglial activation, cortical injury, and functional decline in vivo, compared to ischemia alone. And while GCI was sufficient to induce neutrophil (PMN) activation and recruitment to the post-ischemic CNS, minimal endotoxemia exhibited synergistic effects on markers of systemic inflammation including PMN priming, lung damage, and PMN burden within the lung and other non-ischemic organs including the kidney and liver. Our findings predict that acute interventions geared towards blocking the effects of serologically occult endotoxemia in survivors of cardiac arrest will limit delayed neurodegeneration, multi-organ dysfunction and potentially other features of PCAS. This work also introduces lung-brain coupling as a novel therapeutic target with broad effects on innate immune priming and post-ischemic neurodegeneration following cardiac arrest and related cerebrovascular conditions.
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Project description:In recent decades, solid organ transplantation (SOT) has increased the survival and quality of life for patients with end-stage organ failure by providing a potentially long-term treatment option. Although the availability of organs for transplantation has increased throughout the years, the demand greatly outweighs the supply. One possible solution for this problem is to extend the potential donor pool by using extended criteria donors. However, organs from such donors are more prone to ischemia reperfusion injury (IRI) resulting in higher rates of delayed graft function, acute and chronic graft rejection and worse overall SOT outcomes. This can be overcome by further investigating donor preconditioning strategies, graft perfusion and storage and by finding novel therapeutic agents that could reduce IRI. relaxin (RLX) is a peptide hormone with antifibrotic, antioxidant, anti-inflammatory and cytoprotective properties. The main research until now focused on heart failure; however, several preclinical studies showed its potentials for reducing IRI in SOT. The aim of this comprehensive review is to overview currently available literature on the possible role of RLX in reducing IRI and its positive impact on SOT.
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Project description:OBJECTIVE:Whereas chronic overnutrition is a risk factor for surgical complications, long-term dietary restriction (reduced food intake without malnutrition) protects in preclinical models of surgical stress. Building on the emerging concept that acute preoperative dietary perturbations can affect the body's response to surgical stress, we hypothesized that short-term high-fat diet (HFD) feeding before surgery is detrimental, whereas short-term nutrient/energy restriction before surgery can reverse negative outcomes. We tested this hypothesis in two distinct murine models of vascular surgical injury, ischemia-reperfusion (IR) and intimal hyperplasia (IH). METHODS:Short-term overnutrition was achieved by feeding mice a HFD consisting of 60% calories from fat for 2 weeks. Short-term dietary restriction consisted of either 1 week of restricted access to a protein-free diet (protein/energy restriction) or 3 days of water-only fasting immediately before surgery; after surgery, all mice were given ad libitum access to a complete diet. To assess the impact of preoperative nutrition on surgical outcome, mice were challenged in one of two fundamentally distinct surgical injury models: IR injury to either kidney or liver, or a carotid focal stenosis model of IH. RESULTS:Three days of fasting or 1 week of preoperative protein/energy restriction attenuated IH development measured 28 days after focal carotid stenosis. One week of preoperative protein/energy restriction also reduced plasma urea, creatinine, and damage to the corticomedullary junction after renal IR and decreased aspartate transaminase, alanine transaminase, and hemorrhagic necrosis after hepatic IR. However, exposure to a HFD for 2 weeks before surgery had no significant impact on kidney or hepatic function after IR or IH after focal carotid stenosis. CONCLUSIONS:Short-term dietary restriction immediately before surgery significantly attenuated the vascular wall hyperplastic response and improved IR outcome. The findings suggest plasticity in the body's response to these vascular surgical injuries that can be manipulated by novel yet practical preoperative dietary interventions.
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Project description:Ischemia reperfusion injury (IRI) in organ transplantation remains a significant problem with limited alternative therapeutic options. Organs that undergo significant damage during IRI, particularly those enduring long warm ischemia times, undergo significant delayed graft function (DGF) after reperfusion and tend to have greater complications long term with the onset of chronic rejection. The gas molecule carbon monoxide (CO) has emerged as an agent that can suppress IRI in rodent models of solid organ transplantation. Since the use of CO is a potential therapeutic modality in humans, we tested if CO can prevent DGF in a pig model of kidney transplantation Keywords: stress response, treatment response 18 Samples from pig kidneys, two naïve controls, two timepoints, two conditions, 4 replicates
2009-01-20 | E-GEOD-14373 | biostudies-arrayexpress
Project description:We previously demonstrated that baicalein could protect against liver ischemia/reperfusion (I/R) injury in mice. The exact mechanism of baicalein remains poorly understood. Autophagy plays an important role in protecting against I/R injury. This study was designed to determine whether baicalein could protect against liver I/R injury via induction of autophagy in rats. Baicalein was intraperitoneally injected 1 h before warm ischemia. Pretreatment with baicalein prior to I/R insult significantly blunted I/R-induced elevations of serum aminotransferase levels and significantly improved the histological status of livers. Electron microscopy and expression of the autophagic marker LC3B-II suggested induction of autophagy after baicalein treatment. Moreover, inhibition of the baicalein-induced autophagy using 3-methyladenine (3-MA) worsened liver injury. Furthermore, baicalein treatment increased heme oxygenase (HO)-1 expression, and pharmacological inhibition of HO-1 with tin protoporphyrin IX (SnPP) abolished the baicalein-mediated autophagy and the hepatocellular protection. In primary rat hepatocytes, baicalein-induced autophagy also protected hepatocytes from hypoxia/reoxygenation injury in vitro and the beneficial effect was abrogated by 3-MA or Atg7 siRNA, respectively. Suppression of HO-1 activity by SnPP or HO-1 siRNA prevented the baicalein-mediated autophagy and resulted in increased hepatocellular injury. Collectively, these results suggest that baicalein prevents hepatocellular injury via induction of HO-1-mediated autophagy.
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