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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms by which T cells contribute to the hepatic inflammation during antigen-independent ischemia/reperfusion (I/R) are not fully understood. We analyzed the recruitment of T cells in the postischemic hepatic microcirculation in vivo and tested the hypothesis that T cells interact with platelets and activate sinusoidal endothelial cells, resulting in microvascular dysfunction followed by tissue injury. Using intravital videofluorescence microscopy, we show in mice that warm hepatic I/R (90/30-140 min) induces accumulation and transendothelial migration of CD4+, but not CD8+ T cells in sinusoids during early reperfusion. Simultaneous visualization of fluorescence-labeled CD4+ T cells and platelets showed that approximately 30% of all accumulated CD4+ T cells were colocalized with platelets, suggesting an interaction between both cell types. Although interactions of CD4+/CD40L-/- T cells with CD40L-/- platelets in wild-type mice were slightly reduced, they were almost absent if CD4+ T cells and platelets were from CD62P-/- mice. CD4 deficiency as well as CD40-CD40L and CD28-B7 disruption attenuated postischemic platelet adherence in the same manner as platelet inactivation with a glycoprotein IIb/IIIa antagonist and reduced neutrophil transmigration, sinusoidal perfusion failure, and transaminase activities. Treatment with an MHC class II antibody, however, did not affect I/R injury. In conclusion, we describe the type, kinetic, and microvascular localization of T cell recruitment in the postischemic liver. CD4+ T cells interact with platelets in postischemic sinusoids, and this interaction is mediated by platelet CD62P. CD4+ T cells activate endothelium, increase I/R-induced platelet adherence and neutrophil migration via CD40-CD40L and CD28-B7-dependent pathways, and aggravate microvascular/hepatocellular injury.
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PMID:CD4+ T cells contribute to postischemic liver injury in mice by interacting with sinusoidal endothelium and platelets. 1644 Mar 42

Experiments in rodents have demonstrated an important role for selectins in kidney ischemia-reperfusion injury (IRI). However, the relevance of this in larger mammals, as well as the impact on long-term structure and function is unknown. We tested the hypothesis that small molecule selectin ligand inhibition attenuates IRI, cellular inflammation, and long-term effects on renal interstitial fibrosis. We used a porcine model of kidney IRI and used Texas Biotechnology Corporation (TBC)-1269, a selectin ligand inhibitor. Renal function, tissue inflammation, and tubulointerstitial fibrosis development were evaluated up to 16 weeks. Both warm and cold ischemia models were studied for relevance to native and transplant kidney injury. Pigs treated with TBC-1269 during 45 min of warm ischemia (WI) showed significantly increased glomerular filtration rate compared to control animals. In pigs with severe IRI (WI for 60 min), TBC-1269 treatment during IRI significantly increased renal recovery. Cellular inflammation was strongly reduced, particularly influx of CD4 cells. Quantitative measurement of fibrosis by picrosirius red staining showed strong reduction in TBC-1269-treated groups. TBC-1269 also reduced cold IRI, inflammation, and fibrosis in kidneys preserved for 24 h at 4 degrees C and autotransplanted. The selectin ligand inhibitor TBC-1269 provides a novel and effective approach to attenuate IRI in both warm and cold ischemia in large mammals, in both short and long terms. Selectin ligand inhibition is an attractive strategy for evaluation in human kidney IRI.
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PMID:Protective role of selectin ligand inhibition in a large animal model of kidney ischemia-reperfusion injury. 1662 50

Severe ischemia-reperfusion injury (IRI) predisposes to long-term impairment in kidney function both in patients and experimentally through unknown mechanisms. Given emerging evidence implicating lymphocytes in the pathogenesis of early injury to kidney, liver, and lung after IRI, we hypothesized that kidney IRI would potentially release or expose normally sequestered antigens that would lead to proliferation of antigen-recognizing lymphocytes. This, in turn, would directly participate in progressive kidney injury. To test this hypothesis, we purified splenic lymphocytes from C57BL/6 mice with severe renal IRI or sham operation 6 wk postischemia and transferred these cells to normal mice. Donor mice with IRI had significant fibrosis and cellular inflammation. The recipient mice were followed for 6 or 12 wk. Donor lymphocytes were found to traffic into recipient kidney. Twelve weeks after transfer, kidneys from mice which received IRI-primed lymphocytes exhibited significantly increased urinary albumin excretion compared with lymphocytes from sham mice. Splenic CD3(+), CD4(+), CD3(+)CD25(+), and CD4(+)CD44(+) counts were significantly increased in mice after lymphocyte transfer from IRI mice vs. mice with lymphocytes from sham mice. These data demonstrate that lymphocytes from IRI mice can traffic to recipient kidney and directly mediate albuminuria. These data identify a novel mechanism by which initial kidney injury predisposes to long-term dysfunction and identify lymphocytes as potential therapeutic targets for progressive renal diseases.
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PMID:Transfer of lymphocytes from mice with renal ischemia can induce albuminuria in naive mice: a possible mechanism linking early injury and progressive renal disease? 1675 31

Effects of adenoviral therapy and reduced apoptosis on immune response were investigated in a rat liver transplantation model after prolonged ischemia-reperfusion. Liver donors were treated i.v. either with an adenoviral construct, expressing bcl-2, green-fluorescent-protein, or doxycyclin. Intrahepatic apoptosis was assessed by terminal transferase dUTP nick end labeling assay. The intrahepatic presence of CD4, CD8a, CD163, immunoglobulin (Ig)beta, tumor necrosis factor (TNF)-alpha and myeloperoxidase (MPO) was quantified by realtime polymerase chain reaction at 24 hours and seven days after transplantation. Bcl-2 expression abrogated the TNF-alpha elevation and reduced apoptosis of hepatocytes and sinusoidal endothelial cells as compared to advCMV green fluorescent protein. No effects on CD4, CD8a, CD163 and MPO expression were noticed in bcl-2 pretreated livers, whereas Igbeta was slightly enhanced compared to controls. Adenoviral infected liver grafts trigger an immune response but reduced apoptosis resulted in down-regulation of TNF-alpha. Thus, bcl-2 transfer might simultaneously reduce graft ischemia reperfusion injury and immunogenicity.
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PMID:Inhibition of apoptosis reduces immunogeneic potential of adenoviral-treated syngeneic liver grafts. 1713 Jul 89

The immune response to foreign or self antigens mediates liver damage during viral or autoimmune hepatitis. However, it now appears that also specific antigen-independent liver diseases, where liver damage has been attributed to occur from oxygen radical formation, seem to be mediated by cells of the innate and adaptive immune response. These liver disorders include alcoholic liver disease, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, and ischemia/reperfusion injury that impairs the function of liver grafts. Here it seems that breakdown of the gastrointestinal barrier might increase the concentration of bacterial toxins in the portal blood, which then activate cells of the innate immune system, e. g., Kupffer cells, but, depending on the nature of the toxin, probably also conventional T cells. Invariant NKT cells which specifically recognize glycolipid antigens were supposed to become activated during metabolic disorders related to obesity. However, both steatohepatitis as well as ischemia/reperfusion injury are associated with a Th1 cytokine response characterized by IFNgamma and TNFalpha elevation, that might reflect an NKT cell response on the one hand, but also conventional T lymphocytes, in particular CD4 (+) T cells, are critical for the pathophysiology of these disorders. In 1992 we described a model of T cell-dependent liver injury inducible by the T cell-mitogenic lectin concanavalin A. This model of immune-mediated liver injury was intensively used to study pathophysiological immune effector mechanisms as well as cytokine signaling important for hepatocellular apoptosis, inhibition of apoptosis and regeneration. Recently it became evident that the inflammatory response in this model is regulated by specific cytokine signals as well as by immune regulator cells. The immune-regulatory functions of the liver are of particular interest with respect to the scavenger function of this organ, being continuously exposed to foreign antigenic material from the gut which should be eliminated without causing chronic disease.
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PMID:Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. 1723 22

The aim of this study was to develop a model of chronic rejection of the entire small intestine transplantation and to analyze the features of chronic rejection. Allogenic small bowel transplantation was performed in a rat combination of Lewis to F344. Intestines were procured at the 60th and the 90th day after operation. We compared the semiquantitative score of histological parameters. The immunological components involved in the chronic rejection process were evaluated by immunohistochemical staining and the cytokine levels in grafts. The significant characteristics of the allograft on histology were changes of villous architecture, interstitial fibrosis, leukocyte infiltration, and obliterative arteriopathy. Allografts on the 60th day post-transplantation had more score in inflammatory events, while the grafts on the 90th day after operation had more values in ischemia/fibrotic events. The number of infiltrating CD4, CD8 and macrophage cells in allografts progressively decreased over time. The level of intragraft cytokines such as IL-6, TNF-alpha and IL-10 in the 90th day after transplantation also decreased compared with that in the 60th day. These data suggested that in the early stage (POD 60), there were more active and intense inflammatory events; later (POD 90) allografts manifested less inflammation and more arterial obliteration and fibrosis.
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PMID:Features of chronic allograft rejection on rat small intestine transplantation. 1730 Apr 96

Case reports have previously been published describing various complications of cytomegalovirus (CMV) and mucormycosis in patients with HIV/AIDS. We describe the first case of CMV vasculitis and mucormycosis coinfection resulting in necrotizing myofascial cellulitis in an extremity in late stage HIV/AIDS. In AIDS patients, CMV reactivates when the CD4 count falls to less than 50 cells/microL (normal, 720-1440 cells/microL). Transient episodes of neutropenia in patients with HIV/AIDS who have low CD 4 cell counts are a predisposing factor for mucormycosis. These predisposing conditions were both present in our patient. Our case raises the question of CMV vasculitis leading to tissue ischemia as a possible contributing factor to the mucormycosis superinfection.
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PMID:Cytomegalovirus vasculitis and mucormycosis coinfection in late-stage HIV/AIDS. 1730 93

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 micro, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5% compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39%; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of betaC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-gamma and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.
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PMID:Contribution of CD4+ T cells to the early mechanisms of ischemia- reperfusion injury in a mouse model of acute renal failure. 1740

Previous work has shown that ischemia-reperfusion (IR) injury (IRI) is dependent on CD4(+) T cells from naive mice acting within 24 h. We hypothesize that NKT cells are key participants in the early innate response in IRI. Kidneys from C57BL/6 mice were subjected to IRI (0.5, 1, 3, and 24 h of reperfusion). After 30 min of reperfusion, we observed a significant increase in CD4(+) cells (145% of control) from single-cell kidney suspensions as measured by flow cytometry. A significant fraction of CD4(+) T cells expressed the activation marker, CD69(+), and adhesion molecule, LFA-1(high). Three hours after reperfusion, kidney IFN-gamma-producing cells were comprised largely of GR-1(+)CD11b(+) neutrophils, but also contained CD1d-restricted NKT cells. Kidney IRI in mice administered Abs to block CD1d, or deplete NKT cells or in mice deficient of NKT cells (Jalpha18(-/-)), was markedly attenuated. These effects were associated with a significant decrease in renal infiltration and, in activation of NKT cells, and a decrease in IFN-gamma-producing neutrophils. The results support the essential role of NKT cells and neutrophils in the innate immune response of renal IRI by mediating neutrophil infiltration and production of IFN-gamma.
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PMID:NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. 1744 74

Ischemia/reperfusion injury (IRI) remains an important problem in clinical transplantation. Following ischemia, phosphatidylserine (PS) translocates to surfaces of endothelial cells (ECs) and promotes the early attachment of leukocytes/platelets, impairing microvascular blood flow. Diannexin, a 73 KD homodimer of human annexin V, binds to PS, prevents attachment of leukocytes/platelets to EC, and maintains sinusoidal blood flow. This study analyzes whether Diannexin treatment can prevent cold IRI in liver transplantation. Rat livers were stored at 4 degrees C in UW solution for 24 h, and then transplanted orthotopically (OLT) into syngeneic recipients. Diannexin (200 microg/kg) was infused into: (i) donor livers after recovering and before reperfusion, (ii) OLT recipients at reperfusion and day +2. Controls consisted of untreated OLTs. Both Diannexin regimens increased OLT survival from 40% to 100%, depressed sALT levels, and decreased hepatic histological injury. Diannexin treatment decreased TNF-alpha, IL-1beta, IP-10 expression, diminished expression of P-selectin, endothelial ICAM-1, and attenuated OLT infiltration by macrophages, CD4 cells and PMNs. Diannexin increased expression of HO-1/Bcl-2/Bcl-xl, and reduced Caspase-3/TUNEL+ apoptotic cells. Thus, by modulating leukocyte/platelet trafficking and EC activation in OLTs, Diannexin suppressed vascular inflammatory responses and decreased apoptosis. Diannexin deserves further exploration as a novel agent to attenuate IRI, and thereby improve OLT function/increase organ donor pool.
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PMID:Diannexin, a novel annexin V homodimer, protects rat liver transplants against cold ischemia-reperfusion injury. 1786 64


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