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)

Ischemia/reperfusion during liver transplantation triggers a complex cascade of inflammatory events that may lead to organ dysfunction. Herein, we investigated the consequences of hepatic ischemia/reperfusion on liver dendritic cells. Liver damage was documented by increased levels of serum alanine aminotransferase and by histopathology showing large areas of hepatocyte cytolysis. MHC class II+ CD45-B220 F4/80 dendritic cells were detected in necrotic areas 20 hours after reperfusion. Dendritic cells freshly isolated from reperfused livers displayed a mature phenotype characterized by upregulated expression of B7 costimulatory molecules; MHC-class II, and CD1d molecules. As shown by real-time PCR, IL-10, and TGF-beta mRNA accumulated in liver dendritic cells isolated after reperfusion, whereas IL-12p40 mRNA levels were decreased and IFN-gamma mRNA levels were unchanged. These results suggest that hepatic ischemia/reperfusion results in maturation of dendritic cells, which preferentially produce inhibitory cytokines.
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PMID:The fate of dendritic cells in a mouse model of liver ischemia/reperfusion injury. 1525 11

Inflammation, upregulation of cytokines, proapoptotic molecules, and apoptosis are accepted widely as crucial players in stroke-induced brain damage. Induction of brain tolerance against ischemia by pretreatment with nonlethal stressors (preconditioning) has been found to influence expression of different molecules, in addition to reduction of infarct size. It remains unclear, however, whether and how preconditioning changes expression of cytokines after subsequent brain ischemia. We sought to analyze cortical expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, Fas, and Fas ligand (FasL) mRNA after a transient, focal brain ischemia in rats subjected to preconditioning. The mRNA levels were determined using a semiquantitative RT-PCR in the ischemic and contralateral cortex, separately. Transient ischemia was induced by 90-min middle cerebral artery occlusion (MCAo) and neurologic deficits as well as infarct size were quantified. Preconditioning was carried out by a short-term MCAo or an injection of 3-nitropropionic acid 3 days before MCAo. In both preconditioning paradigms, similar effects on investigated mRNA levels were observed. IL-1beta and IL-6 levels were decreased in tolerant rats compared to those in nontolerant ones. Changes in TNF-alpha, TGF-beta, and Fas levels were comparable independently of tolerance state. FasL mRNA was at similar level in rats subjected to chemical preconditioning but lower after ischemic preconditioning. Our findings demonstrate that both preconditioning methods exert a very similar effect on the expression of investigated cytokines. Interestingly, we observed a selective effect of preconditioning on IL-1beta and IL-6 expression that suggests different functional properties as well as different regulation of analyzed molecules during an induction of the brain tolerance against ischemia.
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PMID:Influence of chemical and ischemic preconditioning on cytokine expression after focal brain ischemia. 1537 97

Fatty livers of obese fa/fa rats are vulnerable to injury when challenged by insults such as endotoxin, ischemia-reperfusion or acute ethanol treatment. The objective of this study was to evaluate whether a high-fat diet can act as a "second hit" and cause progression to liver injury in obese fa/fa rats compared with lean Fa/? rats. Accordingly, obese fa/fa rats and their lean littermates were fed a diet low in fat (12% of total calories) or a diet with 60% calories as lard for 8 weeks. Hyperglycemia and steatohepatitis occurred in the fa/fa rats fed the high-fat diet. This was accompanied by liver injury as assessed by alanine aminotransferase, hematoxilin and eosin staining, increased TNFalpha and stellate cell-derived TGFbeta, collagen deposition, and up-regulation of alpha-smooth muscle actin. Active MMP13 decreased in fa/fa rats independently of the diet, and TIMP1 expression increased with the high-fat diet, especially in fa/fa rats. Although UCP2 expression was higher in fa/fa rats regardless of the diet, minor changes in ATP levels were observed. Oxidative stress occurred in the fa/fa rats fed the high-fat diet as lipid peroxidation and protein carbonyls were elevated, while glutathione and antioxidant enzymes were very low. Expression and activity of cytochrome P450 2E1 and xanthine oxidase activity were down-regulated in fa/fa compared with Fa/? rats, and no effect was seen by the high-fat diet. However, NADPH oxidase activity increased 2.5-fold in fa/fa rats fed with the high-fat diet. In summary, a high-fat diet induces liver injury in fa/fa rats leading to periportal fibrosis. A role for oxidative stress is suggested via increased NADPH oxidase activity, lipid peroxidation, protein carbonyl formation, and low antioxidant defense.
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PMID:A high-fat diet leads to the progression of non-alcoholic fatty liver disease in obese rats. 1552 5

Transforming growth factor (TGF)-beta1 and a number of TGF-beta-responsive genes are transiently enhanced following induction of ischemic acute renal failure (ARF) in the rat. The mRNA and protein expression of TGF-beta receptors were analyzed in postischemic rat kidneys by ribonuclease protection, in situ hybridization, and immunohistochemistry. TGF-betaRI and -RII were enhanced within 3 days of ischemia-reperfusion (I/R) injury and remained elevated for up 7 days post-I/R; TGF-beta receptor expression was localized primarily in regenerating tubules within the outer medulla. A neutralizing TGF-beta antibody exacerbated cellular proliferation observed on day 3 postischemia but had no effect on day 1 or 2. TGF-beta antibody treatment had no measurable effect on loss of renal function or the restoration of renal function during the recovery response for up to 35 days postsurgery. However, ischemic injury resulted in modest renal hypertrophy that is due, in part, to in an increase in the number of interstitial cells in the postischemic kidney. Immunohistochemistry showed that several of these cells stained positively for the fibroblast-specific marker, S100A4 positive. Anti-TGF-beta treatment substantially attenuated the renal hypertrophy, interstitial cellularity, and S100A4-positive cells present at 35 days post-I/R. Finally, TGF-beta immunoneutralization attenuated the loss of renal vascular density following recovery from I/R injury. These data suggest that the TGF-beta/TbetaR system is enhanced in the postischemic kidney. However, the current study failed to identify a prominent role for this system in the repair of proximal tubules following ARF. In contrast, the activation of this system may play an important role in the long-term structure of the postischemic kidney by influencing microvascular structure and interstitial cellularity.
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PMID:Transforming growth factor-beta in acute renal failure: receptor expression, effects on proliferation, cellularity, and vascularization after recovery from injury. 1553 65

The role of monocytes/macrophages in the pathogenesis of ischemia-reperfusion injury (IRI) is unknown. We sought to determine whether activation of macrophage adenosine 2A (A(2A)) receptors (A(2A)Rs) mediates tissue protection. We subjected C57Bl/6 mice infused with clodronate [dichloromethylene bisphosphonate (Cl(2)MBP)] to IRI (32 min of ischemia followed by 24 h of reperfusion) to deplete them of macrophages. IRI induced an elevation of plasma creatinine that was reduced with Cl(2)MBP (26% of control). Adoptive transfer of murine RAW 264.7 cells reconstituted injury, an effect blocked significantly by A(2A) agonists (27% of plasma creatinine from mice reconstituted with macrophages). Macrophages subjected to A(2A) knockout by small interfering RNA were adoptively transferred to macrophage-depleted mice and reconstituted injury (110% of control mice); however, the increase in plasma creatinine was blocked by A(2A) agonists (20% of vehicle treatment). Finally, the A(2A) agonist effect on IRI was blocked in macrophage-depleted A(2A)-knockout mice reconstituted with wild-type RAW 264.7 cells. RNase protection assays 24 h after IRI demonstrated that macrophages are required for IL-6 and TGF-beta mRNA induction. However, A(2A) agonist-mediated tissue protection is independent of IL-6 and TGF-beta mRNA. We conclude that the full extent of IRI requires macrophages and that A(2A) agonist-mediated tissue protection is independent of activation of macrophage A(2A)Rs.
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PMID:Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. 1556 71

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

Accelerated atherosclerosis in dialysis patients is characterized by severe vascular calcification, and the magnitude of vascular calcification is associated with increased cardiovascular mortality. Calcification-dependent arterial stiffness is considered to be a major determinant of cardiac failure in uremia. Fetuin-A/alpha(2)-Heremans-Schmid glycoprotein is an abundant serum protein with powerful calcification inhibitory properties. Fetuin-A deficiency was recently linked to cardiovascular mortality in dialysis patients. Fetuin-A knockout (fetuin-KO) mice spontaneously develop widespread soft tissue calcification, including significant myocardial calcification, whereas larger arteries are spared. Therefore, this investigation offers the unique opportunity to study the functional role of isolated myocardial calcification independent of arterial stiffness by assessing the hemodynamics of fetuin-KO mice. Cardiac output in fetuin-KO mice was lower than in wild-type mice (fetuin-KO 1.81 +/- 0.18 versus WT 2.45 +/- 0.29 ml/min per g; P < 0.005), and fetuin-KO mice were refractory to dobutamine stimulation. Left ventricular relaxation was significantly impaired in fetuin-KO hearts with the relaxation index reduced by 23% (P < 0.005). After ischemia, fetuin-KO hearts displayed a continuous decline in left ventricular developed pressure after the initial phase of reperfusion, resulting in 77 +/- 15% of preischemic left ventricular developed pressure (P < 0.05 versus wild-type). In fetuin-KO mice, dystrophic cardiac calcification, with myocardial calcium contents increased 60-fold, was associated with profound induction of profibrotic TGF-beta and downstream collagen and fibronectin mRNA synthesis. In conclusion, independent of arterial stiffness, calcification-associated "myocardial stiffness" characterized by cardiac fibrosis, diastolic dysfunction, impaired tolerance to ischemia, and catecholamine resistance thus may constitute an underestimated cardiovascular risk factor that contributes to cardiac failure in calcification-prone states.
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PMID:Myocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-A-deficient mice. 1617

The pathogenesis of skin scleroderma (LS) is still unknown. Disturbances of vessels system, connective tissue metabolism and humoral and cellular immunological response is observed. Antinuclear antibodies are detected in 30-80% of patients with different types of skin scleroderma. They are present more often in patients with disseminated lesions and linear type of LS compared to morphoea au plaque. In our own analysis 28.5% of patients had also antibodies directed against Borrelia burgdorferi. It is believed that the injury of endothelial cells and proliferation in medial part of small vessels - which both lead to chronic ischemia - are the earliest disturbances observed in histopathological examination of the skin taken from systemic as well as from skin scleroderma patients. During last few years, there were some interesting reports concerning functional changes of endothelial cells which led to disturbances in tension of vessels smooth muscles. Free radicals - in genetically predispose people--can also provoke scleroderma lesions through their injury action on endothelial cells and stimulation of fibroblasts. In morphoea, the process of fibrosis begins around vessels. Deposition of connective tissue matrix is observed, especially collagen type I and III. This stimulation of fibroblasts as well as accumulation of connective tissue matrix are secondary to some stimulatory factors. These are: PDF, bFGF, TGFbeta and some cytokines. In morphoea patients serum levels of IL-1, IL-2, IL-4, IL-6 and IL-8 were elevated. In literature, levels and production of collagenases were decreased, although more authors say that tissue inhibitors of metalloproteinases are the main factor in fibrosis. The analysis of data tends to suspicion that enormous fibrosis observed in different types of scleroderma can be the result of increased production of collagen and other components of connective tissue as well as their incomplete degradation. Presented clinical and laboratory data show how many different factors influence etiopathogenesis of morphoea.
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PMID:[Pathogenesis of skin scleroderma--literature review]. 1633 38

Aged hearts exhibit reduced tolerance to ischemia-reperfusion, together with altered structure and post-ischemic remodelling. The molecular bases of such changes are unclear. Using cDNA microarrays and quantitative RT-PCR we characterized shifts in gene expression patterns with aging in normoxic and post-ischemic (20 min global ischemia, 60 min reperfusion) murine hearts (young: 2-4 months; aged: 16-18 months). We identified an age-associated up-regulation of transcripts involved in cell death, oxygen transport and metabolism in normoxic hearts. Down-regulated transcripts were involved in transporter activity, protein binding and hydrolase activity, changes in MAPK, WNT and TGF-beta signalling with aging were also observed. Ischemic stress generated a much greater degree of contractile impairment and cellular damage in aged vs. young hearts. This was associated with a substantially modified transcriptional response, with selective changes in Ca2+, WNT, NOTCH and G-protein coupled receptor signalling paths in aged vs. young hearts. Despite some common responses to ischemia in young and aged hearts (induction of heat shock protein transcripts), aging selectively modified ischemic responses of immediate early genes, and genes involved in modulating apoptosis and remodelling/angiogenesis. In summary, aging is associated with shifts in cardiovascular gene expression consistent with the phenotypic features of older hearts. Reduced tolerance with age may be related to modification of signalling (particularly WNT and TGF-beta), and shifts in expression of immediate early genes, and genes important in control of cell death/survival, angiogenesis, and cardiac remodelling.
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PMID:Age-associated shifts in cardiac gene transcription and transcriptional responses to ischemic stress. 1634 35

Clinical trials of therapeutic angiogenesis for the treatment of cardiovascular ischemia have failed to meet the expectations with the use of single growth factors, namely VEGF and bFGF. We show here that a bovine bone-derived growth factor mixture (GFM) of TGFbetas, BMPs, and no more than 0.1% aFGF can initiate a dose-dependent angiogenic response in subcutaneously implanted Growth Factor Reduced Matrigel plugs that includes abundant smooth muscle actin positive (SMA+) tubes and functional CD31+, red blood cell filled, capillaries. Tube forming activity of the single factors, recombinant bFGF and bone-derived TGF-beta2, were comparable to GFM, but only the bone-derived factors were able to create a larger fraction of SMA+ tubes than Matrigel alone at an equal dose. Basic FGF formed a greater number of RBC-filled capillaries within the plugs than GFM or TGF-beta2 at the highest doses, although GFM created RBC-filled capillaries that penetrated deeper into the plugs than bFGF. However, bFGF showed the greatest number of non-cell-lined, RBC-filled pools, suggestive of vessel rupture, and the largest number of plugs showing signs of fluid accumulation in the form of large, cell-lined clefts in the implants. TGF-beta2 showed less RBC-filled pools, but a significant number of implants with signs of fluid accumulation. At high doses of GFM penetration by blood vessels and mesenchymal cells was obstructed by cartilage development within the plugs accompanied by a prominent band of SMA+ granulation tissue with abundant RBC-filled capillaries encapsulating the implants. Thus, GFM is also capable of dramatically remodeling the vascular system in the interstitial space surrounding the plug. These results show that GFM is capable of inducing the formation of a more mature vascular system than that formed by the single factors bFGF and TGFbeta-2. Natural mixtures of TGFbetas, BMPs, and FGFs may have superior clinical utility in therapeutic angiogenesis applications.
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PMID:A bone-derived mixture of TGF beta-superfamily members forms a more mature vascular network than bFGF or TGF-beta 2 in vivo. 1640 May 22


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