Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Numerous clinical trials using anti-inflammatory agents for patients with acute respiratory distress syndrome (ARDS) have failed despite efficacy in acute animal models. This underscores the necessity of developing a clinically relevant model of ARDS. Initially, we attempted to induce lung injury in pigs by fecal peritonitis only. When this was unsuccessful, we designed a two-hit model of ischemia/reperfusion (I/R) injury followed by fecal peritonitis to create a clinically applicable model of ARDS. The initial study consisted of Yorkshire swine [group 1, fecal clot (FC), n = 4] that were followed clinically after intraperitoneal placement of a fecal (0.5 mL/kg) blood (2 mL/kg) clot. Blood was sampled daily for cultures, a complete blood count, a lactate level, and various cytokine expression determined by enzyme-linked immunosorbent assay (ELISA). Pigs were treated with antibiotics and fluids, placed on a ventilator before sacrifice to obtain hemodynamic and pulmonary parameters, and underwent histologic lung assessment. Additionally, bronchoalveolar lavage fluid was obtained for protein concentration and cytokine levels. Once it was evident that no lung injury had occurred, we designed a more severe model. A second group of Yorkshire swine [group 2, superior mesenteric artery (SMA) + FC, n = 4] underwent SMA occlusion for 30 min (I/R) followed by intraperitoneal placement of a FC as in the initial group. These pigs were monitored more invasively and continuously in an intensive care setting for 48 h and followed, treated, and assessed in a similar fashion to group 1. Group 1 (FC) pigs survived 9 days and showed signs of sepsis (bacteremia with polymicrobial organisms), an inflammatory response in the form of elevated cytokines, yet no physiologic or histologic evidence of lung injury. Group 2 (SMA + FC) pigs demonstrated more severe sepsis, a significantly increased cytokine response compared with animals in the FC group, and physiologic signs of progressive pulmonary injury. Pigs in the SMA + FC group were sacrificed at 48 h after clinical deterioration (significant decline in oxygenation) and demonstrated pathologic evidence of lung injury indicated by increased bronchoalveolar lavage fluid protein, diffuse and thickened alveolar septae, hyaline membrane formation, and pulmonary edema. The addition of a second "hit" (SMA occlusion, I/R) to a FC sepsis model resulted in severe lung injury that developed within a 3-day period. To our knowledge, this is the first large animal experiment that definitively and consistently causes insidious onset ARDS in pigs. By closely paralleling the clinical development of pulmonary injury, this model should prove invaluable in the study of human ARDS.
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PMID:The development of acute respiratory distress syndrome after gut ischemia/reperfusion injury followed by fecal peritonitis in pigs: a clinically relevant model. 1566 27

The local ischemia-reperfusion (I/R) process gains a systemic nature and affects distal organs. The remote effects of I/R are most frequently observed in the lungs and pulmonary damage may vary from acute lung injury with mild dysfunction to severe respiratory failure or the acute respiratory distress syndrome. In this hind limb I/R induced experimental lung injury model two groups of rats as IR and ILO were determined. Both groups underwent 60 min of ischemia and 120 min of reperfusion. While ILO group received iloprost in saline, IR group received only saline before reperfusion period intravenously. Serum myeloperoxidase (MPO) activity, malondialdehyde (MDA) levels and total antioxidant capacity (TAC) and lung tissue MPO activity, MDA levels and Na+-K+ ATPase activity were measured and light microscopic analyses of lung specimens were performed. The MPO activities in serum and lung homogenates were found to be significantly decreased in ILO group (P < or = 0.01). The MDA levels in lung homogenates were found to be significantly decreased in ILO group (P < or = 0.01), but the decreases were not significant in serum MDA levels (P=0.052). Serum TAC and lung tissue Na+-K+ ATPase activity levels were found to be increased in ILO group compared to IR group (P < or = 0.01). Lung histology showed marked improvement by iloprost compared to the IR group in this study. Iloprost has been found to be effective in attenuating ischemia reperfusion-induced remote organ damage, in this case, lung injury, in rats.
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PMID:The influence of iloprost on acute lung injury induced by hind limb ischemia-reperfusion in rats. 1577 6

Inhibition of poly(ADP-ribosyl)ation in oxidative stress-related pathologies has recently emerged as a very effective anti-inflammatory intervention in animal models of arthritis, colitis, diabetes and shock. Recent data from three laboratories also support the role of poly(ADP-ribose) polymerase-1 (PARP-1) activation in asthma. Similarly to other inflammatory conditions, the protective effects of PARP inhibition and the PARP-1 knock out phenotype in asthma models have been attributed to inhibition of inflammatory signal transduction (mainly via NF-kappaB) and of oxidative stress-induced cell dysfunction and tissue injury. Here I discuss the complex role of poly(ADP-ribosyl)ation in the regulation of inflammatory cell migration, chemokine and cytokine production and expression of other inflammatory mediators (inducible nitric oxide synthase, matrix metalloproteinases) in asthma. The role of PARP-1 in other oxidative stress-related lung diseases such as asbestosis, silicosis, acute respiratory distress syndrome and ischemia-reperfusion injury is also reviewed.
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PMID:Poly(ADP-ribosyl)ation in asthma and other lung diseases. 1591 36

Necrotizing enterocolitis (NEC) is a common, life-threatening neonatal gastrointestinal disease; it affects approximately 11% of extremely premature neonates. The etiology of NEC is multifactorial. Risk factors may roughly be grouped into four main categories: prematurity; transient ischemia of the intestine; local/systemic inflammation predisposing the bowel to injury, and therapeutic interventions. Recent studies have shown that carrier state of genetic polymorphisms may be associated with perinatal morbidity, including NEC. In perinatal disorders, the significance of genetic variants of cytokines, the renin-angiotensin-aldosterone system, and surfactant proteins have been investigated most widely. Positive findings indicate the implication of genetic polymorphisms of proinflammatory cytokines in premature birth; angiotensin converting enzyme in perinatal adaptation and angiotensin type 1 receptor in the closure of ductus arteriosus; surfactant proteins A and B in respiratory distress syndrome; interleukin (IL)-6 in sepsis, and IL-4-receptor alpha chain and IL-18 in NEC. This review provides an insight into the genetics of NEC and summarizes genetic data in light of pathologic processes leading to NEC.
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PMID:Genetic basis for necrotizing enterocolitis--risk factors and their relations to genetic polymorphisms. 1614 53

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.
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PMID:Chemically modified tetracycline prevents the development of septic shock and acute respiratory distress syndrome in a clinically applicable porcine model. 1620 20

We report acute thromboembolic events in a 14-year-old boy with Down syndrome and repaired atrioventricular septal defect. He presented with sudden onset of bilateral lower limb ischemia. Transesophageal echocardiography detected a thrombus in the right atrium. An arterial saddle embolus was removed following bilateral iliac embolectomy. Despite anticoagulation, he presented again with sudden bilateral lower limb ischemia and respiratory distress. Multiple pulmonary emboli and a thrombus in the right atrium were noted on imaging studies. An arterial embolus was removed from the abdominal aorta at the bifurcation. To our knowledge, this is the first report of a child or adolescent with a repaired congenital heart lesion and arterial embolism requiring embolectomy. This association and possible etiological factors are discussed.
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PMID:Saddle arterial embolus in a patient with Down syndrome. 1640 56

Oxidative stress defines an imbalance in production of oxidizing chemical species and their effective removal by protective antioxidants and scavenger enzymes. Evidence of massive oxidative stress is well established in adult critical illnesses characterized by tissue ischemia-reperfusion injury and by an intense systemic inflammatory response such as during sepsis and acute respiratory distress syndrome. Oxidative stress could exacerbate organ injury and thus overall clinical outcome. We searched MEDLINE databases (January 1966 to June 2005). For interventional studies, we accepted only randomized trials. Several small clinical trials have been performed in order to reduce oxidative stress by supplementation of antioxidants alone or in combination with standard therapies. These studies have reported controversial results. Newer large multicenter trials with antioxidant supplementation should be performed, considering administration at an early stage of illness and a wider population of critically ill patients.
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PMID:The role of oxidative stress in adult critical care. 1644 54

HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
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PMID:High-mobility group box 1 (HMGB1) protein: friend and foe. 1651 9

Common inhaled and intravenous anesthetics except the barbiturate are recommended for the patients with bronco-constrictive lung disease because of their bronco-dilating property. However there are pharmacological potency differences between individual anesthetics. The halogenated inhaled anesthetics and propofol exert antiinflammatory effect on acute lung injury and acute respiratory distress syndrome in the laboratory level, but further study is required for future clinical application. These anesthetics also have an organ protective effect on the ischemia reperfusion lung injury, and their clinical application is expected in the lung transplantation surgery.
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PMID:[Lung protection with anesthetics]. 1671 10

Brain death is associated with complex hemodynamic, endocrine, and metabolic dysfunction that can lead to major complications with the potential donor. Untreated, this can progress to cardiovascular collapse with loss of valuable organs for transplantation. We hypothesized that brain death-related complications would have no effect on the number of organs donated if an aggressive donor management protocol was in place. We identified all successful organ donations between January 2000 and December 2003 and evaluated them for brain death-associated complications (defined as vasopressor requirement, coagulopathy, diabetes insipidus, cardiac ischemia, lactic acidosis, renal failure, and acute respiratory distress syndrome) and donated organs per donor. Sixty-nine organ donors were identified. Complications identified were as follows: intravenous vasopressor requirement in 97.1 per cent, coagulopathy in 55.1 per cent, thrombocytopenia in 53.6 per cent, diabetes insipidus in 46.4 per cent, cardiac ischemia in 30.4 per cent, lactic acidosis in 24.6 per cent, renal failure in 20.3 per cent, and acute respiratory distress syndrome in 13 per cent. There was no significant effect of complications on the average number of organs harvested, with the exception of an increase in organs harvested in the presence of diabetes insipidus. With the implementation of an aggressive organ donor management protocol, these complications can be effectively managed with no impact on the number of organs harvested for transplant.
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PMID:Complications of brain death: frequency and impact on organ retrieval. 1671 88


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