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)

The ileal pouch anal anastomosis (IPAA) procedure has become the preferred surgical option for most patients with ulcerative colitis who require surgical removal of the colorectum. The vast majority of patients with this new anatomy will either not develop pouchitis or develop a few discrete episodes of acute pouchitis. However approximately one fourth of patients will develop recurrent pouchitis, with 5% being categorized as chronic pouchitis requiring maintenance therapy or, on rare occasion, pouch excision. Factors that are associated with an increased risk of pouchitis include primary sclerosing cholangitis, extraintestinal manifestations, and nonsmokers. Controversy surrounds other risk factors such as extent of colitis, backwash ileitis, preoperative pANCA levels, and carrying a specific allele for IL-1 receptor antagonist. The etiology of pouchitis is unknown, but theories range from genetic susceptibility, bacterial overgrowth, ischemia, and fecal stasis, to a recurrence of ulcerative colitis in the pouch, a missed diagnosis of Crohn's disease, or possibly a novel third form of inflammatory bowel disease. Some patients with symptoms of pouchitis will not have inflammation of the pouch, but rather, irritable pouch syndrome. Thus, endoscopic investigation with biopsy is important for declaring whether a patient has pouchitis. Indeed, the more commonly used scores, such as the pouch disease activity index, incorporate both endoscopic and histologic criteria. Not surprisingly, treatment options for patients with pouchitis resemble that of regular inflammatory bowel disease, although there have only been a few controlled trials. Antibiotics are the mainstay of therapy, with metronidazole and ciprofloxacin demonstrating benefit in controlled trials. Probiotics are effective for maintaining remission of pouchitis. Mesalamine, corticosteroids, and immunomodulators have been used with some success. Occasionally, patients with well-documented ulcerative colitis as the indication for IPAA will develop what appears to be Crohn's disease of the pouch, on the basis of granulomatous inflammation, pre-pouch ileitis, or fistulae. The treatment is similar to Crohn's disease, including the use of infliximab. Dysplasia within the pouch mucosa itself is quite rare. Reports of dysplasia occurring in patients with IPAA are usually due to neoplastic change within the residual cuff of rectal or transition zone mucosa just below the pouch, rather than in the ileal mucosa of the pouch. With further elucidation of the genetic basis for inflammatory bowel disease, we should be able to more accurately classify patients with ulcerative colitis and Crohn's disease genotypically. Hopefully, this will also bring more clarity to the heterogeneous population of patients with pouchitis and allow for more focused therapeutic strategies.
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PMID:The diagnosis and treatment of pouchitis in inflammatory bowel disease. 1511 32

The mechanisms of anti-ischemic effects of PGE1 in patients with peripheral arterial occlusive disease (PAD) are probably complex and clearly not limited to a direct vasodilator action. In addition to the known effects on blood flow, viscosity, fibrinolysis and platelet aggregation, the compound also inhibits monocyte and neutrophil function, suggesting that PGE1 will also have anti-inflammatory effects. Recent research has detected additional actions of PGE1 and prostacyclin analogs which might be relevant to its clinical efficacy. This includes inhibition of expression of adhesion molecules (E-selectin, ICAM-1, and VCAM-1), release of inflammatory cytokines (TNFalpha, MCP-1), matrix components and generation and release of growth factors (CYR61, CTGF). These actions may also contribute to the long-term effects of PGE1, particularly in more advanced stages of PAD. Gene-expression experiments with chemically stable prostacyclins and PGE1 suggest that several genes in vascular smooth muscle cells and fibroblasts are modified by prostaglandins at the transcriptional level. This includes TNFalpha-induced VCAM expression in vascular smooth muscle cells which appears to be inhibited via the prostaglandin EP2 receptor as well as IL-1-induced expression of the type-1 collagen gene in fibroblasts. Thus, regulation of gene transcription by PGE1 may contribute to tissue protection in critical ischemia of the lower limbs.
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PMID:Mechanisms of anti-ischemic action of prostaglandin E1 in peripheral arterial occlusive disease. 1546 Oct 62

Inflammatory processes play a crucial role in the pathogenesis of atherosclerosis and other vascular disorders. We hypothesized that ischemia of the ductus arteriosus might initiate an active inflammatory response that could play a role in ductus remodeling and permanent closure. To test this hypothesis, we studied effects of postnatal ductus construction on inflammatory processes and remodeling in late-gestation fetal and newborn baboons, and preterm newborn baboons. After postnatal ductus constriction, the expression of several genes known to be essential for atherosclerotic remodeling [vascular cell adhesion molecule (VCAM)-1, E-selectin, IL-8, macrophage colony stimulating factor-1, CD154, interferon-gamma, IL-6, and tumor necrosis factor-alpha] was increased in the ductus wall. We were unable to detect intercellular adhesion molecule (ICAM)-1, ICAM-2, P-selectin, monocyte chemoattractant protein-1, or IL-1 by either real-time PCR or immunohistochemistry. VCAM-1, which is newly expressed by luminal cells of the closed ductus, is an important ligand for the mononuclear cell adhesion receptor VLA4. After postnatal constriction, VLA4+ monocytes/macrophages (CD68+ and CD14+) and, to a lesser extent, T-lymphocytes adhered to the ductus wall. Neutrophils and platelets were not observed. The extent of postnatal neointimal remodeling (both endothelial cell layering and subendothelial space thickening) was associated with the degree of mononuclear cell adhesion. Similarly, the extent of vasa vasorum ingrowth correlated with the invasion of CD68+ cells, from the adventitia into the muscle media. Based on these data, we conclude that the inflammatory response following postnatal ductus constriction may be as necessary for ductus remodeling as it is for atherosclerotic remodeling.
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PMID:The role of monocyte-derived cells and inflammation in baboon ductus arteriosus remodeling. 1561 59

Ischemic-reperfusion injury mediated by free radicals and neutrophils is the principal pathway for tissue injury and death. Cytokines influence activity of various cell types during the inflammatory process. In this study, expression of selected proinflammatory cytokines was examined in primary and secondary ischemia in the rat gracilis flap model. Sixty Sprague-Dawley rats were used in the study. Primary ischemia of each gracilis flap was induced by clamping its vascular pedicle for 1 hour. The flap was then replaced and allowed to reperfuse. Twenty-four hours later, a secondary ischemia was induced via vascular clamping for 4 hours. All muscle flaps were biopsied at 4 hours and 18 hours after primary ischemia. After secondary ischemia, each flap was biopsied immediately postevent, at 4 hours, and at 18 hours. Expression of tumor necrosis factor (TNF-alpha), interleukin (IL-1beta), and platelet-derived growth factor (PDGF) mRNA was determined by RT-PCR in each case. An equal sample size of gracilis muscle flaps, elevated in an identical fashion but not subjected to vascular clamping, was examined for baseline gene expression. Results showed that TNF-alpha gene expression was significantly up-regulated at 18 hours after secondary ischemia. IL-1 gene expression was up-regulated at 4 hours after primary ischemia, and was greatest at 4 hours after secondary ischemia. PDGF expression was up-regulated immediately after secondary ischemia, then at 4 hours after secondary ischemia (P < 0.05), and down-regulated during reperfusion. This study delineated changes in the expression of TNF-alpha, IL-1beta, and PDGF mRNA, in both primary and secondary ischemia and reperfusion episodes at several critical time points.
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PMID:The expression of proinflammatory cytokines in the rat muscle flap with ischemia-reperfusion injury. 1572 43

Brain phosphatidylcholine (PC) levels are regulated by a balance between synthesis and hydrolysis. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1alpha/beta) activate phospholipase A(2) (PLA(2)) and PC-phospholipase C (PC-PLC) to hydrolyze PC. PC hydrolysis by PLA(2) releases free fatty acids including arachidonic acid, and lyso-PC, an inhibitor of CTP-phosphocholine cytidylyltransferase (CCT). Arachidonic acid metabolism by cyclooxygenases/lipoxygenases is a significant source of reactive oxygen species. CDP-choline might increase the PC levels by attenuating PLA(2) stimulation and loss of CCT activity. TNF-alpha also stimulates proteolysis of CCT. TNF-alpha and IL-1beta are induced in brain ischemia and may disrupt PC homeostasis by increasing its hydrolysis (increase PLA(2) and PC-PLC activities) and inhibiting its synthesis (decrease CCT activity). The beneficial effects of CDP-choline may result by counteracting TNF-alpha and/or IL-1 mediated events, integrating cytokine biology and lipid metabolism. Re-evaluation of CDP-choline phase III stroke clinical trial data is encouraging and future trails are warranted. CDP-choline is non-xenobiotic, safe, well tolerated, and can be considered as one of the agents in multi-drug treatment of stroke.
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PMID:Cytidine 5'-diphosphocholine (CDP-choline) in stroke and other CNS disorders. 1575 28

Activation of the A2A adenosine receptor (A(2A)R) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A(2A)R on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester (ATL313; 3 microg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-gamma-inducible protein-10, IL-1alpha, IL-1-beta, IL-1Ralpha, IL-18, IL-6, and IFN-gamma), or histological criteria. ATL313, which is highly selective for the A(2A)R, produces more liver protection of chimeric BMT mice than 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid, which has similar affinity for the A(2A)R and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A(2A)R on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
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PMID:A2A adenosine receptors on bone marrow-derived cells protect liver from ischemia-reperfusion injury. 1581 35

Ischemia and reperfusion (I/R) is an important pathologic phenomenon that has not been completely defined from the perspective of the molecular signaling pathways developed immediately at its inception to minutes and hours thereafter. From the practical point of view, we have divided I/R into 3 phases: phase I, which occurs seconds to minutes after the injury and is associated with changes dependent on the activation of phospholipases, intracellular calcium, eicosanoids, other lipid molecules, protein kinases, inducible nitric oxide synthase, and the expression of preformed adhesion molecules like P-selectin; phase II, which occurs minutes to hours after I/R injury and is associated with the active transcription of protein synthesis of molecules like inflammatory cytokines (mainly tumor necrosis factor-alpha and interleukin 1) starting their signaling downstream from the membrane into the cytoplasm where kinases will be activated and send signals to the nucleus for the activation of transcription factors and further continuing with the inflammatory event; and phase III, which occurs several hours to days after I/R and is associated with the appearance of molecular chronic mechanisms of protection like the presence of anti-inflammatory cytokines of the IL-10 type, late adhesion molecules, and other growth factors such as TGF-beta. This completes the whole molecular event related to I/R injury.
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PMID:Molecular signaling pathways in ischemia/reperfusion. 1585 24

Bacterial infection is implicated in the selective CNS white matter injury associated with cerebral palsy, a common birth disorder. Exposure to the bacterial endotoxin LPS produced death of white matter glial cells in isolated neonatal rat optic nerve (RON) (a model white matter tract), over a 180-min time course. A delayed intracellular Ca(2+) concentration ([Ca(2+)](i)) rise preceded cell death and both events were prevented by removing extracellular Ca(2+). The cytokines TNF-alpha or IL-1beta, but not IL-6, mimicked the cytotoxic effect of LPS, whereas blocking either TNF-alpha with a neutralizing Ab or IL-1 with recombinant antagonist prevented LPS cytotoxicity. Ultrastructural examination showed wide-scale oligodendroglial cell death in LPS-treated rat optic nerves, with preservation of astrocytes and axons. Fluorescently conjugated LPS revealed LPS binding on microglia and astrocytes in neonatal white and gray matter. Astrocyte binding predominated, and was particularly intense around blood vessels. LPS can therefore bind directly to developing white matter astrocytes and microglia to evoke rapid cell death in neighboring oligodendroglia via a calcium- and cytokine-mediated pathway. In addition to direct toxicity, LPS increased the degree of acute cell death evoked by ischemia in a calcium-dependent manner.
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PMID:Acute lipopolysaccharide-mediated injury in neonatal white matter glia: role of TNF-alpha, IL-1beta, and calcium. 1597 42

Interleukin (IL)-1 and IL-18 belong to the IL-1 family. IL-18 deficiency has been shown to confer moderate protection after hypoxia-ischemia (HI) in the immature brain, while the contribution of the two isoforms of IL-1 (IL-1alpha and IL-1beta) in neonatal HI brain injury has not been investigated previously. The aim of this study was to examine the contribution of the different members of the IL-1 family to neonatal HI damage. Unilateral HI was induced at postnatal day 9 in IL-1beta, IL-1beta18, and IL-1alphabeta knockout and wild-type mice and brain injury was evaluated 1 week later. IL-1beta18-deficient mice showed 17% reduction in brain injury, while no significant reduction in injury was detected between any of the other groups. These results indicate that IL-18, but not IL-1beta, or the combination of IL-1alpha and IL-1beta, is a contributor to HI injury in the immature brain.
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PMID:Combined deficiency of IL-1beta18, but not IL-1alphabeta, reduces susceptibility to hypoxia-ischemia in the immature brain. 1604 48

Streptozotocin administration in newborn rats (nSTZ-rats) leads to adults with mild insulin deficiency and normoglycemia, and is accepted as a model of type 2 diabetes. We examined possible differences in the production of inflammatory mediators between healthy and nSTZ-rats after ischemia-reperfusion (I-R). Two-month-old control and nSTZ-rats were randomly separated into control and intestinal I-R groups. After reperfusion, samples were obtained from the portal vein (PV) infrahepatic cava vein (ICV), suprahepatic cava vein (SCV), jejunal wall, and pancreas. Nitric oxide (NO), lipid hydroperoxides (LPO), tumor necrosis factor alpha (TNF-alpha), 60 kDa receptor (sTNF-R1), 80 kDa (sTNF-R2), and intercellular adhesion molecule-1 (ICAM-1), were determined. After I-R, nSTZ-rats showed increased plasma concentrations of LPO, NO, ICAM-1 (0.5141 +/- 0.083 vs 0.024 +/- 0.003, ICV; 0.574 +/- 0.075 vs 0.023 +/- 0.003, SCV; 0.528 +/- 0.067 vs 0.027 +/- 0.003 PV; ng/ml), TNF-alpha (42.4 +/- 5.7 ICV, 248.4 +/- 28.2 SCV, and 33.6 +/- 4.0 PV. In n STZ-rats, vs 4.36 +/- 0.57, 4.74 +/- 0.77, and 3.16 +/- 0.32, respectively, in control rats; pg/ml), and sTNF-R1. Both TNF-alpha and NO plasma levels were higher in SCV than in ICV and PV after I-R. In addition, after I-R, jejunal wall of nSTZ-rats showed an increase of TNF-alpha IL-1, and IL-10 levels. A pre-existing state of glucose intolerance intensifies the inflammatory response after intestinal I-R.
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PMID:Glucose intolerance modifies the inflammatory response after intestinal ischemia-reperfusion. 1608 24


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