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)

Based on successful induction of donor-specific unresponsiveness by alloantigenic stimulation in several animal models of acute rejection, we hypothesized that similar immune manipulations would also inhibit the evolution of chronic rejection and transplant vasculopathy. To induce immune tolerance, DA rats received a PVG heart allograft and were immunosuppressed with cyclosporine for 30 d. At day 100 the animals were challenged with a PVG aortic allograft after either 1 or 18 h of cold ischemia. 8 wk after the aortic transplantation, the grafts were investigated for morphological changes, infiltrating cells, apoptosis, and Fas-Fas ligand expression. Control allografts showed advanced transplant arteriosclerosis, whereas tolerance-induced aortic allografts displayed reduced neointimal formation, less medial atrophy, fewer apoptotic cells, and fewer Fas- and FasL-expressing cells. Prolonged ischemic storage time did not profoundly alter the morphological changes of the allografts. Fas expression was found in T cells, macrophages, vascular smooth muscle cells, and endothelial cells, whereas FasL was expressed mainly by T cells and macrophages. FasL mRNA expression was evident throughout the entire allograft wall. In conclusion, induction of allospecific tolerance can effectively prevent transplant arteriosclerosis. Cold ischemia damage does not abrogate the beneficial effect of tolerance, but creates a separate identity of mainly endothelial lesions. Furthermore, Fas-mediated apoptosis appears to be involved in the pathological lesions seen in chronic rejection.
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PMID:Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis. 963 24

The Fas/Fas ligand (FasL) system plays an important role in the induction of lymphoid apoptosis and has been implicated in the suppression of immune responses. Recently, there has been renewed interest in immune privilege, as it was shown that two privileged sites (the eye and testes) constitutively express FasL, which kills lymphoid cells that invade these areas. We have established murine FasL-transgenic mice (B6) under the control of the cardiac alpha-myosin heavy chain promotor, and transplanted FasL-expressing F1(B6 x C3H/HeJ) heart grafts into syngeneic (F1) and allogeneic (C3H/HeJ) recipients. FasL-expressing F1 heart allografts placed in C3H/HeJ recipients as well as FasL-expressing F1 isografts placed in nontransgenic and FasL-transgenic F1 were more rapidly rejected, and their survival was much shorter than that of nontransgenic control F1 allografts placed in C3H/HeJ. Native control and FasL-expressing hearts looked normal in mice up to 8 wk of age on hematoxylin-eosin staining. Control heart allografts undergoing ordinally acute rejection showed moderate focal lymphocyte infiltrates, while FasL-expressing F1 allografts and isografts showed massive hemorrhage, edema, and massive neutrophil infiltration as early as 1 day after transplantation. In conclusion, FasL expression and surgical procedure (ischemia/reperfusion) were synergistic in the induction of accelerated heart graft rejection, while allogenicity was not necessary. It may be necessary to find ways of controlling neutrophilic reaction/apoptosis in infiltrating lymphocytes to use FasL in clinical organ transplantation.
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PMID:Accelerated rejection of Fas ligand-expressing heart grafts. 988 28

Cell death by apoptosis is thought to be involved in various pathophysiological situations involving the liver. Indeed, an understanding of apoptosis is becoming increasingly helpful for understanding disease and for patients' care. In this article, we review current scientific and clinical concepts of apoptosis, including death factors such as Fas ligand and tumor necrosis factor, apoptotic signal transduction mechanisms, and the role of intracellular proteinases called caspases. We also discuss apoptosis in the liver, as related to ischemia/reperfusion injury, cholestasis, and cancer, circumstances which physicians often face in the field of the liver surgery.
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PMID:Apoptosis and the liver: relevance for the hepato-biliary-pancreatic surgeon. 993 90

Brief periods of in vitro hypoxia/ischemia induce apoptosis of cultured renal epithelial cells, but the underlying mechanisms remain unknown. We show that partial ATP depletion (approximately 10-65% of control) results in a duration-dependent induction of apoptosis in Madin-Darby canine kidney (MDCK) cells, as evidenced by internucleosomal DNA cleavage (DNA laddering and in situ nick end labeling), morphological changes (cell shrinkage), and plasma membrane alterations (externalization of phosphatidylserine). The ATP-depleted cells display a significant upregulation of Fas, Fas ligand, and the Fas-associating protein with death domain (FADD). Exogenous application of stimulatory Fas monoclonal antibodies also induces apoptosis in nonischemic MDCK cells, indicating that they retain Fas-dependent pathways of programmed cell death. Furthermore, cleavage of poly(ADP)ribose polymerase (PARP) is evident after ATP depletion, indicating activation of caspases. Indeed, the apoptotic cells display a significant increase in caspase-8 (FLICE) activity. Finally, apoptosis induced by ATP depletion is ameliorated by pretreatment with inhibitors of caspase-8 (IETD), caspase-1 (YVAD), or caspase-3 (DEVD) but is not affected by inhibitors of serine proteases (TPCK). Our results indicate that partial ATP depletion of MDCK cells results in apoptosis and that Fas- and caspase-mediated pathways may play a critical role.
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PMID:Partial ATP depletion induces Fas- and caspase-mediated apoptosis in MDCK cells. 1036 72

Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor (TNF), are expressed after acute hemodynamic overloading and myocardial ischemia/infarction. To define the role of TNF in the setting of ischemia/infarction, we performed a series of acute coronary artery occlusions in mice lacking one or both TNF receptors. Left ventricular infarct size was assessed at 24 h after acute coronary occlusion by triphenyltetrazolium chloride (TTC) staining in wild-type (both TNF receptors present) and mice lacking either the type 1 (TNFR1), type 2 (TNFR2), or both TNF receptors (TNFR1/TNFR2). Left ventricular infarct size as assessed by TTC staining was significantly greater (P < 0.005) in the TNFR1/TNFR2-deficient mice (77.2% +/- 15.3%) when compared with either wild-type mice (46.8% +/- 19.4%) or TNFR1-deficient (47.9% +/- 10.6%) or TNFR2-deficient (41.6% +/- 16.5%) mice. Examination of the extent of necrosis in wild-type and TNFR1/TNFR2-deficient mice by anti-myosin Ab staining demonstrated no significant difference between groups; however, the peak frequency and extent of apoptosis were accelerated in the TNFR1/TNFR2-deficient mice when compared with the wild-type mice. The increase in apoptosis in the TNFR1/TNFR2-deficient mice did not appear to be secondary to a selective up-regulation of the Fas ligand/receptor system in these mice. These data suggest that TNF signaling gives rise to one or more cytoprotective signals that prevent and/or delay the development of cardiac myocyte apoptosis after acute ischemic injury.
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PMID:Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. 1077 46

The Fas molecule, also designated APO-1/CD95, belongs to the tumor necrosis factor (TNF) receptor family. It is a widely expressed membrane-anchored protein that induces apoptosis by Fas/Fas ligand (Fas-L) mediation. It was reported that Fas-mediated apoptosis plays an important role in regulation of the immune system, systemic inflammatory response, and ischemia/reperfusion injury. A soluble form of Fas (sFas) is produced either through the proteolytic cleavage of membrane-bound receptors or by alternative splicing, and sFas is thought to be implicated in apoptosis. In addition, sFas released damaged cells, and elevated serum levels of sFas reflect systemic tissue damage. To examine the specificity of sFas production during cardiac surgery with cardiopulmonary bypass, we serially measured the serum sFas levels in 13 patients during and after surgery. Blood samples were obtained before surgery, at the end of cardiopulmonary bypass, at the end of surgery, and at 12 h after surgery. Levels of serum sFas were determined by sandwich ELISA. Seven patients undergoing other types of surgeries served as controls. Although increased sFas was not observed in the control group, a significantly higher sFas level was detected in cardiac surgical patients at the end of surgery than before surgery (p = 0. 028), and the level decreased at 12 h after surgery. A significant correlation was observed between the maximum sFas values and the length of surgery (r = 0.659, p = 0.012) and cardioplegic arrest (r = 0.559, p = 0.046). Elevated serum sFas levels were observed in patients undergoing cardiac surgery, and these serum sFas levels reflect the severity of a surgery. sFas may play an important role in the pathophysiology of surgical damage caused by cardiac surgery with cardiopulmonary bypass.
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PMID:Transient rise in serum soluble Fas (APO-1/CD95) in patients undergoing cardiac surgery. 1097 Dec 50

The present study investigates the molecular apoptotic pathway in germ cells following acute ischemia of the rat testis. Rats were subjected to ischemia-inducing torsion and testes were harvested after reperfusion. Apoptotic cells were identified with an antibody to single-stranded DNA. Seminiferous tubule RNA was examined by RNase protection assay or by reverse transcriptase-polymerase chain reaction (RT-PCR) for the presence and regulation of apoptotic molecules. Proteins from seminiferous tubules were used for Western blot analysis of cytochrome c. Germ cell apoptosis was maximal at 24 h after repair of torsion. Germ cells in stages II-III of the seminiferous epithelium cycle were the predominant early responders. The RNase protection assays revealed that Bcl-X(L) was the prominent mRNA species. Caspases 1, 2, 3, and Bax mRNA were consistently upregulated; however, the time of upregulation after torsion was variable. The Bcl-X(L) and Bcl-X(S) mRNAs were less consistently upregulated and there was no evidence for upregulation of Fas or Bcl-2. Fas ligand (FasL) was not detected by RNase protection assay, but RT-PCR revealed a significant increase in FasL expression 4 h after the repair of torsion. Western blot analysis for cytochrome c release demonstrated a significant increase 4 h after the repair of torsion. Results suggest that germ cell apoptosis following ischemia/reperfusion of the rat testis is initiated through the mitochondria-associated molecule Bax as well as Fas-FasL interactions.
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PMID:Molecular pathway of germ cell apoptosis following ischemia/reperfusion of the rat testis. 1105 53

Apoptosis of germ cells is very common in normal and injured mammalian testes. The aim of this study was to examine the possible involvement of the Fas and Fas ligand (FasL) system in the induction of germ cell apoptosis in normal and ischemia-reperfusion testes of adult mice. Apoptosis was assessed by the TUNEL method and by DNA gel electrophoresis. Fas and FasL mRNAs were detected by Northern blotting and reverse transcription polymerase chain reaction techniques, and proteins were analyzed by Western blotting and immunohistochemistry. Apoptosis of germ cells was identified in the normal testis especially around stages XI and XII, whereas the expression of Fas and FasL was largely confined to Leydig cells and Sertoli cells, respectively. However, in the testes reperfused after 1 h of ischemia, a high number of TUNEL-positive cells were identified in parallel with increased Fas-positive germ cells, whereas FasL expression in Sertoli cells was almost constant irrespective of the duration of reperfusion. Moreover, i.p. injection of anti-Fas antibody, which blocks the interaction between Fas and FasL, inhibited apoptosis, as indicated by the reduced number of TUNEL-positive cells, except for apoptosis at stages XI and XII. Our results indicate that the Fas/FasL system mediates apoptosis of spermatogenic cells in the injured testis but not spontaneous apoptosis in the normal testis.
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PMID:Expression of Fas and Fas ligand in normal and ischemia-reperfusion testes: involvement of the Fas system in the induction of germ cell apoptosis in the damaged mouse testis. 1120 12

Previously we reported that ischemia results in apoptosis and is accompanied by phosphorylation on Tyr-701 and increased expression and transcriptional activity of the signal transducer and activator of transcription-1 (STAT-1). In the present study, we show that exposure of cardiomyocytes to ischemia induced the phosphorylation of STAT-1 at another site, Ser-727. Moreover, STAT-1 is critical for the induction of Fas receptor and Fas ligand expression by ischemia/reperfusion (I/R). Transcriptional activation of Fas and FasL was dependent on Ser-727 of STAT-1 but was independent of Tyr-701. Similarly, Ser-727 but not Tyr-701 was required for enhancement of cardiomyocyte cell death by STAT-1 during I/R. In addition, inhibition of the p38 pathway prevented the induction and transcriptional activation of Fas and FasL in cardiac cells exposed to I/R, whereas inhibition of p42/p44 MAPK had no effect. Finally, I/R also induced phosphorylation of STAT-1 on Ser-727 and expression of Fas/FasL in ventricular myocytes in the intact heart ex vivo. These results indicate that Fas/FasL genes and apoptosis are activated by STAT-1 in cardiac myocytes exposed to I/R and these effects are dependent on the Ser-727 but not the Tyr-701 phosphorylation sites of STAT-1.
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PMID:Induction of apoptosis and Fas receptor/Fas ligand expression by ischemia/reperfusion in cardiac myocytes requires serine 727 of the STAT-1 transcription factor but not tyrosine 701. 1130 87

Apoptosis, or programmed cell death, and the elimination of apoptotic cells are crucial factors in the maintenance of liver health Apoptosis allows hepatocytes to die without provoking a potentially harmful inflammatory response In contrast to necrosis, apoptosis is tightly controlled and regulated via several mechanisms, including Fas/Fas ligand interactions, the effects of cytokines such as tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta), and the influence of pro- and antiapoptotic mitochondria-associated proteins of the B-cell lymphoma-2 (Bcl-2) family. Efficient elimination of apoptotic cells in the liver relies on Kupffer cells and endothelial cells and is thought to be regulated by the expression of certain cell surface receptors. Liver disease is often associated with enhanced hepatocyte apoptosis, which is the case in viral and autoimmune hepatitis, cholestatic diseases, and metabolic disorders. Disruption of apoptosis is responsible for other diseases, for example, hepatocellular carcinoma. Use and abuse of certain drugs, especially alcohol, chemotherapeutic agents, and acetaminophen, have been associated with increased apoptosis and liver damage. Apoptosis also plays a role in transplantation-associated liver damage, both in ischemia/reperfusion injury and graft rejection. The role of apoptosis in various liver diseases and the mechanisms by which apoptosis occurs in the liver may provide insight into these diseases and suggest possible treatments.
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PMID:Apoptosis in diseases of the liver. 1134 18


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