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)

Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA(4) stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mphi) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA(4), LXB(4), the aspirin-triggered LX (ATL) epimer, 15-epi-LXB(4), and a stable synthetic analogue 15(R/S)-methyl-LXA(4) stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M phi) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA(4), LXB(4), 15(R/S)-methyl-LXA(4), and 15-epi-LXB(4) of 2.5 to 10 micro g/kg. Non-phlogistic LX-stimulated phagocytosis by M phi was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-beta(1) (TGF-beta(1)). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M phi to beta 1,3-glucan, suggesting a novel M phi-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA(4) receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-beta(1) release. These data provide the first demonstration that LXA(4), LXB(4), ATL, and LX stable analogues rapidly promote M phi phagocytosis of PMN in vivo and support a role for LX as rapidly acting, pro-resolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.
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PMID:Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. 1223 38

Ischemia-reperfusion (I/R) is thought to upregulate the expression and activity of matrix metalloproteinases (MMPs), which regulate myocardial and vascular remodeling. Previous studies have shown that transforming growth factor-beta(1) (TGF-beta(1)) can attenuate myocardial injury induced by I/R. TGF-beta(1) is also reported to suppress the release of MMPs. To study the modulation of MMP-1 by TGF-beta(1) in I/R myocardium, Sprague-Dawley rats were given saline and subjected to 1 h of myocardial ischemia [total left coronary artery (LCA) ligation] followed by 1 h of reperfusion (n = 9). Parallel groups of rats were pretreated with recombinant TGF-beta(1) (rTGF-beta(1), 1 mg/rat, n = 9) before reperfusion or exposure to sham I/R (control group). I/R caused myocardial necrosis and dysfunction, indicated by decreased first derivative of left ventricular pressure, mean arterial blood pressure, and heart rate (all P < 0.01 vs. sham-operated control group). Simultaneously, I/R upregulated MMP-1 (P < 0.01). Treatment of rats with rTGF-beta(1) reduced the extent of myocardial necrosis and dysfunction despite I/R (all P < 0.01). rTGF-beta(1) treatment also inhibited the upregulation of MMP-1 in the I/R myocardium (P < 0.05). To determine the direct effect of MMP-1 on the myocardium, isolated adult rat myocytes were treated with active MMP-1, which caused injury and death of cultured myocytes, measured as lactate dehydrogenase release and trypan blue staining, in a dose- and time-dependent manner (P < 0.05). Pretreatment with PD-166793, a specific MMP inhibitor, attenuated myocardial injury and death induced by active MMP-1. The present study for the first time shows that MMP-1 can directly cause myocyte injury or death and that attenuation of myocardial I/R injury by TGF-beta(1) may, at least partly, be mediated by the inhibition of upregulation of MMP-1.
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PMID:TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1. 1267 26

Blood vessel growth after birth is limited to two major processes. Angiogenesis is the growth of new capillaries by sprouting or intussusception. The major stimulus for angiogenesis is ischemia. In contrast, arteriogenesis describes the remodeling and growth of collateral arteries from a preexisting arteriolar network. Arteriogenesis is induced after the occlusion of a major artery which induces hemodynamic and mechanical effects on the collateral vessel wall which occur with increasing blood flow velocity due to the low pressure at the reentrant site of the collateral vessel. A variety of different cytokines that act by stimulating endothelial and smooth muscle cell proliferation and migration or recruitment and activation of monocytes have been identified to stimulate angiogenesis and/or arteriogenesis (i.e., MCP-1, FGF-2, TGF-beta, VEGF, and GM-CSF). Several clinical trials have been published in that field to suggest the feasibility and safety of treatment with such cytokines or their genes. However, the results indicate that further studies are needed before proangiogenic and proarteriogenic therapies are ready for clinical application.
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PMID:Influence of inflammatory cytokines on arteriogenesis. 1285 53

Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by means of the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. Over the last years, the cytokine termed Transforming Growth Factor-beta 1 (TGF-beta 1) has been found to be strongly up regulated in the central nervous system following ischemia-induced brain damage. Recent studies have shown a neuroprotective activity of TGF-beta 1 against ischemia-induced neuronal death. In vitro, TGF-beta 1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta 1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
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PMID:[Does transforming growth factor-beta (TGF-beta) act as a neuroprotective agent in cerebral ischemia?]. 1291 Jun 29

1. Necrosis and apoptosis are the two fundamental hallmarks of neuronal death in stroke. Nevertheless, thrombolysis, by using the recombinant serine protease t-PA, remains until now the only approved treatment of stroke in man. 2. Over the last years, the cytokine termed Transforming Growth Factor-beta1 (TGF-beta1) has been found to be strongly up-regulated in the central nervous system following ischemia-induced brain damage. 3. Recent studies have shown a neuroprotective activity of TGF-beta1 against ischemia-induced neuronal death. In vitro, TGF-beta1 protects neurons against excitotoxicity by inhibiting the t-PA-potentiated NMDA-induced neuronal death through a mechanism involving the up-regulation of the type-1 plasminogen activator inhibitor (PAI-1) in astrocytes 4. In addition, TGF-beta1 has been recently characterized as an antiapoptotic factor in a model of staurosporine-induced neuronal death through a mechanism involving activation of the extracellular signal-regulated kinase 1/2 (Erk1/2) and a concomitant increase phosphorylation of the antiapoptotic protein Bad. 5. Altogether, these observations suggest that either TGF-beta signaling or TGF-beta1-modulated genes could be good targets for the development of new therapeutic strategies for stroke in man.
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PMID:Transforming growth factor-beta and ischemic brain injury. 1451 14

Ischemic preconditioning is a phenomenon that describes how a sublethal ischemic insult can induce tolerance to subsequent ischemia. This phenomenon has been observed after focal or global ischemia in different animal models. However, the hypothesis that bacterial infection might lead to neuronal tolerance to injury has not been investigated. To mimic cerebral bacterial infection, we injected bacterial lipopolysaccharide (LPS) in the right dorsal hippocampus, followed 24 hours later by an excitotoxic lesion using kainic acid in the mouse model. Quantification of lesion size after cresyl violet counterstaining revealed that LPS pretreatment afforded neuroprotection to CA3 neurons against KA challenge. To investigate the events underlying this protection, we studied the cytokine profile induced after LPS injection. Interleukin (IL)-1 beta and transforming growth factor beta 1 (TGF-beta 1) were the main cytokines expressed at 24 hours after LPS injection. Because IL-1 beta has been described as deleterious in acute injury, we decided to investigate the function of TGF-beta 1. An adenovirus expressing a constitutively active form of TGF-beta 1 was injected intracerebrally 1 week before the induction of excitotoxic lesion, and neuronal protection was observed. To confirm the neuroprotective role of TGF-beta 1, the TGF-beta 1 adenovirus was replaced by recombinant human TGF-beta 1 protein and total neuroprotection was observed. Furthermore, the antibody-mediated blocking of TGF-beta 1 action prevented the protective effect of pretreatment with LPS. We have demonstrated in vivo that the cerebral tolerance phenomenon induced by LPS pretreatment is mediated by TGF-beta 1 cytokine.
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PMID:Transforming growth factor-beta 1-mediated neuroprotection against excitotoxic injury in vivo. 1452 28

Ischemia in various organs and tissues takes place during and as a direct result of multiple trauma (MT). Bone marrow-derived endothelial progenitor cells (EPCs) are involved in neovascularization after ischemic incidences. Here, we report that serum derived from patients with MT stimulates differentiation of EPCs in vitro from peripheral blood mononuclear cells (PBMCs). EPCs were identified by DiL-Acetyl-LDL-uptake with concomitant UEA-I-lectin binding. A significant increase in EPC numbers was noted when PBMCs were cultivated for 72 h with the serum of MT patients (n = 25) obtained at 5 days. Furthermore, serum from MT patients enhanced the functional acting of EPCs to form prevascular structures in matrigel. Reverse transcription polymerase chain reaction analysis revealed gene expression of transforming growth factor (TGF)-beta1- and vascular endothelial growth factor (VEGF) receptors 1 and 2. Reverse transcription polymerase chain reaction analysis was based on further cultivated cell preparations, which contained at least 80% EPCs. Moreover, the addition of recombinant VEGF or low concentrations of TGF-beta increased EPC differentiation. In addition, neutralization of TGF-beta1 and of VEGF165 in MT serum using specific antibodies resulted in a significant decrease in EPC differentiation. Our data indicate that TGF-beta1 and VEGF165 play a pivotal role for EPC differentiation induced by serum of polytrauma patients.
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PMID:Serum derived from multiple trauma patients promotes the differentiation of endothelial progenitor cells in vitro: possible role of transforming growth factor-beta1 and vascular endothelial growth factor165. 1467 78

The mechanisms that control the phagocytic activities of microglia and macrophages during disorders of the nervous system are largely unknown. In the present investigation, we assessed the functional role of transforming growth factor (TGF)beta2 in vitro and studied TGFbeta-2mRNA and protein expression in two CNS lesion paradigms in vivo characterized by fundamental differences in microglia/macrophage behaviour: optic nerve crush exhibiting slow, and focal cerebral ischemia exhibiting rapid phagocytic transformation. Furthermore, we used sciatic nerve crush injury as a PNS lesion paradigm comparable to brain ischemia in its rapid phagocyte response. In normal and degenerating optic nerves, astrocytes strongly and continuously expressed TGF-beta2 immunoreactivity. In contrast, TGF-beta2 was downregulated in Schwann cells of degenerating sciatic nerves, and was not expressed by reactive astrocytes in the vicinity of focal ischemic brain lesions during the acute phagocytic phase. In line with its differential lesion-associated expression pattern, exogenous TGF-beta2 suppressed spontaneous myelin phagocytosis by microglia/macrophages in a mouse ex vivo assay of CNS and PNS Wallerian degeneration. In conclusion, we have identified TGF-beta2 as a nervous system intrinsic cytokine that could account for the differential regulation of phagocytic activities of microglia and macrophages during injury.
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PMID:Lesion-associated expression of transforming growth factor-beta-2 in the rat nervous system: evidence for down-regulating the phagocytic activity of microglia and macrophages. 1499 37

The present study compared the short-term and long-term neuroprotective and neurobehavioral effects of transforming growth factor beta-1 (TGF beta-1) after hypoxic-ischemic injury in adult rats. TGF beta-1 (10 ng) or vehicle were administered intracerebroventricularly (i.c.v.) 2 h after hypoxia-ischemia. Adhesive removal test was assessed after 10 or 40 days, and the neuronal outcome then determined. TGF beta-1 significantly increased the area of intact cortex compared with vehicle 10 days after the injury, with a significant improvement in neurological function. In contrast, after 40 days recovery TGFbeta-1 neither improved neuronal outcome nor neurological function, suggesting TGFbeta-1 can transiently improve functional and histological recovery from hypoxia-ischemia.
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PMID:TGF beta-1 and neurological function after hypoxia-ischemia in adult rats. 1507 15

We have previously demonstrated that pretreatment with bone morphogenetic protein 7 (BMP7), a trophic factor in the TGFbeta superfamily, reduces ischemia-induced brain infarction induced by middle cerebral artery ligation in rats. Since the mitogen-activated protein kinase (MAPK) pathway is involved in many TGFbeta-mediated responses, we examined the interaction of BMP7 and MAPK in primary cultures obtained from the cerebral cortex of E16-17 rat embryos. Lactate dehydrogenase (LDH) in the media was used as an index of cell death. BMP7 did not alter LDH levels at low concentration (1.25 nM), but exhibited increased cellular toxicity at higher concentration (>12.5 nM). BMP7 at the low concentration significantly attenuated H2O2-induced increases in LDH activity and decreases in neuronal density. Pharmacological interactions were used to examine if MAPK was involved in this response. BMP7-induced protection was antagonized by the p42,44 MAPK kinase inhibitors PD98059 and U0125. The p38 MAPK antagonist SB203580, and their inactive analog SB202474, also attenuated BMP7-induced protection, suggesting that the interaction with p38 MAPK is nonspecific. Previous studies have indicated that SB202474 has inhibitory effects on other protein kinases. We found that the protein kinase C inhibitor chelerythrine antagonized BMP7-induced protection against H2O2. Western blot analysis indicated that BMP7 increased phosphorylation of p42,44 MAPK and PKC. Taken together, our data suggest that BMP7 is neuroprotective at low concentrations in primary cortical cell culture. The protective effects of BMP7 may involve the activation of p42,44 MAPK and PKC.
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PMID:Mediation of BMP7 neuroprotection by MAPK and PKC IN rat primary cortical cultures. 1512 17


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