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)

Attraction of mononuclear cells to sites of inflammation requires a close interplay of the inflammatory signal presented via chemokines and specific receptors on effector cells. First studies on acute renal transplant rejection demonstrated the involvement of CC-chemokines, such as RANTES, MIP-1alpha, MIP-1beta and MCP-1, as well as CXC-chemokines such as IL-8 and IP-10, correlating with expression of the corresponding chemokine receptors, CCR1, CCR5 and CCR2 as well as CXCR3. Since then, the pathophysiologic relevance has been extended to chronic allograft nephropathy and transplant glomerulopathy. Chemokine expression can be triggered by different stimuli, e.g. brain death, ischemia, HLA-mismatch and infection. Furthermore, anti-inflammatory chemokines have been identified. Chemokine receptor 7, e.g. enhances homing of lymphocytes to lymphatic tissues and the Duffy antigen receptor, DARC, a non-specific receptor that binds and inactivates different chemokines. While measurement of chemokine expression in clinical transplantation may facilitate the differential diagnosis of allograft dysfunction, knowledge of the chemokine network has also widened the understanding of transplant rejection and opened novel therapeutic approaches. Observations from humans with mutations of the chemokine network as well as transplantation of animals with targeted deletions in this system suggest that manipulations of chemokine signalling may improve the success rates of transplantation. Blocking chemokines unselectively with Met-RANTES or specifically with small molecule inhibitors of various chemokine receptors has lead to improved outcome in animal models. Currently, first human trials are under way to investigate drugs that stimulate lymphocyte homing. Inhibitors of CCR1 and CCR5 are being tested for other human diseases and may eventually be available in transplantation. Nonetheless, chemokine blockade my rather serve as an adjunct in the management of transplant recipients than a new "magic bullet".
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PMID:Chemokines and chemokine receptors in renal transplantation--from bench to bedside. 1744 76

Endothelial progenitor cells (EPCs) are essential in vasculogenesis and wound healing, but their circulating and wound level numbers are decreased in diabetes. This study aimed to determine mechanisms responsible for the diabetic defect in circulating and wound EPCs. Since mobilization of BM EPCs occurs via eNOS activation, we hypothesized that eNOS activation is impaired in diabetes, which results in reduced EPC mobilization. Since hyperoxia activates NOS in other tissues, we investigated whether hyperoxia restores EPC mobilization in diabetic mice through BM NOS activation. Additionally, we studied the hypothesis that impaired EPC homing in diabetes is due to decreased wound level stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1alpha expression in cutaneous wounds. Hyperoxia increased BM NO and circulating EPCs, effects inhibited by the NOS inhibitor N-nitro-L-arginine-methyl ester. Administration of SDF-1alpha into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, and wound healing. Thus, hyperoxia reversed the diabetic defect in EPC mobilization, and SDF-1alpha reversed the diabetic defect in EPC homing. The targets identified, which we believe to be novel, can significantly advance the field of diabetic wound healing.
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PMID:Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. 1747 53

Chemokine signaling plays an important role in the postischemic inflammatory response. Overlapping pathways involving reactive oxygen intermediates, Toll-like receptor (TLR) activation, the complement cascade and the nuclear factor (NF)-kappaB system induce both CXC and CC chemokines in ischemic tissues. Reperfusion accentuates chemokine expression promoting an intense inflammatory reaction. ELR-containing CXC chemokines regulate neutrophil infiltration in the ischemic area, whereas CXCR3 ligands may mediate recruitment of Th1 cells. CC chemokines, on the other hand, induce mononuclear cell infiltration and macrophage activation. Evidence suggests that chemokine signaling mediates actions beyond leukocyte chemotaxis and activation, regulating angiogenesis and fibrous tissue deposition. Effective repair of ischemic tissue is dependent on a well-orchestrated cellular response and on timely induction and suppression of chemokines in a locally restricted manner. This manuscript reviews the evidence suggesting a role for chemokine-mediated effects in ischemia/reperfusion and discusses the potential significance of these interactions in injury and repair of ischemic tissues.
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PMID:Chemokines in ischemia and reperfusion. 1747 84

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the alpha7nAChR, as attested by the absence of protection in alpha7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-alpha and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic alpha7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.
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PMID:Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway. 1752 28

Chemokines (chemotactic cytokines) are important in the recruitment of leukocytes to injured tissues and, as such, play a pivotal role in arteriogenesis and the tissue response to ischemia. Hind limb ischemia represents a complex model with arteriogenesis (collateral artery formation) occurring in tissues with normal perfusion while areas exhibiting ischemic necrosis undergo angiogenesis and skeletal muscle regeneration; monocytes and macrophages play an important role in all three of these processes. In addition to leukocyte trafficking, chemokines are produced by and chemokine receptors are present on diverse cell types, including myoblasts, endothelial, and smooth muscle cells. Thus, the chemokine system may have direct effects as well as inflammatory-mediated effects on arteriogenesis, angiogenesis, and skeletal muscle regeneration. This article reviews the complexity of the hind limb ischemia model and the role of the chemokine system in arteriogenesis and the tissue response to ischemia. Special emphasis will be placed on the roles of monocytes/macrophages and CCL2/monocyte chemotactic protein-1 (MCP-1) in these processes.
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PMID:The chemokine system in arteriogenesis and hind limb ischemia. 1754 24

Emerging research suggests that oxidant-driven transcription of key cytokine/chemokine networks within the myocardium plays a crucial role in producing ischemia-reperfusion (I/R) injury. We recently showed that activation of hypoxia-inducible factor-1 (HIF-1) attenuated cardiac I/R injury. Diminished injury in these prior studies was associated with significant reductions in circulating interleukin-8 levels, suggesting that HIF-1 may play an important role in modulating postischemic cardiac inflammation. In the current study, we examined the role of HIF-1 activation in modulating proinflammatory chemokine [macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant factor (KC), and lipopolysaccharide-induced CXC chemokine (LIX)] and adhesion molecule [intercellular adhesion molecule (ICAM)-1] expression in murine cardiomyocytes in vitro (HL-1 cell line) and in intact murine hearts following in vivo I/R injury. Our results show that HIF-1 activation induced both pharmacologically by the prolyl hydroxylase inhibitor dimethyloxallyl glycine and via small-interfering RNA (siRNA)-mediated prolyl-4 hydroxylase-2 (P4HA2) gene silencing significantly attenuated tumor necrosis factor-alpha-induced chemokine (KC and LIX) and ICAM-1 expression in cardiomyocytes. In vivo, postischemic hearts obtained from animals receiving the P4HA2 siRNA (HIF-1 activation) exhibited significantly reduced CXC chemokine (MIP-2, KC, and LIX), CC chemokine (monocyte chemoattractant protein-1), and ICAM-1 expression when compared with postischemic hearts from either saline I/R controls or postischemic hearts from animals receiving a nontargeting control siRNA (no HIF-1 activation). Diminished chemokine and adhesion molecule expression in HIF-1-activated postischemic hearts was associated with significantly reduced polymorphonuclear leukocyte infiltration and myocardial infarct size (>60% reduction P4HA2 siRNA I/R vs. saline I/R, P < 0.001, n = 6). In conclusion, these results demonstrate for the first time that HIF-1 activation following infusion of siRNA to P4HA2 plays a key role in modulating I/R-associated cardiac inflammatory responses.
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PMID:Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium. 1754 79

Hypoxic-ischemic (HI) brain injury in the perinatal period causes significant morbidity. Minocycline (MN) is a tetracycline derivative that has reduced brain injury in various animal models of neurodegeneration, including perinatal ischemia. To determine whether MN can modulate the expression of chemokine receptors and interleukin-10 (IL10) in a model of neonatal brain injury, we produced an HI insult to the right cerebral hemisphere (ipsilateral) of the 7-day-old rat (PD7) by right common carotid artery ligation and 2.25 hr of hypoxia in 8% oxygen. MN (45 mg/kg, i.p.) or vehicle (PBS) was injected twice: 2 days and immediately before the HI insult. At 0, 1, 3, and 24 hr and 14 days after HI, total RNA from the ipsilateral and contralateral (exposed to hypoxia only) hemispheres was extracted, reverse transcribed, and amplified with gene-specific primers using a semiquantitative RT-PCR for macrophage inflammatory protein-1alpha), interferon-inducible protein (IP-10), C-C chemokine receptor 5 (CCR5; MIP-1alpha receptor), C-X-C chemokine receptor 3 (CXCR3; IP-10 receptor), and IL10. We found that, in the ipsilateral hemisphere, a significant (P < 0.05) increase in MIP-1alpha, IP-10, CCR5, and CXCR3 mRNA levels was observed. MN treatment decreased mRNA levels for CCR5 and CXCR3. In contrast, the levels of antiinflammatory cytokine IL10 were markedly decreased as a result of HI insult. Treatment with MN, however, had no effect on IL10. We conclude that MN decreased proinflammatory chemokine receptor expression but had little or no influence on the expression of antiinflammatory cytokine IL10. These effects confirm the antiinflammatory effect of MN in neonatal HI brain injury.
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PMID:Minocycline modulates chemokine receptors but not interleukin-10 mRNA expression in hypoxic-ischemic neonatal rat brain. 1754 54

Chemokines are a family of small, structurally related cytokines that regulate trafficking of different subsets of leukocytes, thus critically regulating inflammation. The chemokine system influences allograft biology at 3 main levels: 1) the process of ischemia-reperfusion injury, 2) the induction of transplant tolerance, and 3) the pathogenesis of acute rejection and chronic allograft nephropathy. Accordingly, following ischemia/reperfusion in a rat model, CXCR2 produced at the graft level attracts and activates granulocytes, which in turn promotes graft damage. Moreover, in some experimental models CCR4 recruits T regulatory cells and mediates transplant tolerance. Furthermore, the discovery of the involvement of CXCR3 in the induction of the alloresponse to transplant suggests that this chemokine receptor might represent an important target for treatment of both acute rejection and chronic allograft nephropathy. Indeed, CXCR3 ligands play a pivotal role in the initiation and amplification of host alloresponses and also alter vascular cell functions, which explains their critical role not only in the development of acute rejection, but also in the pathogenesis of chronic allograft nephropathy, where both immune- and nonimmune- mediated mechanisms are involved. Finally, we have recently demonstrated that the pretransplant serum level of the CXCR3 ligand IP-10/CXCL10 is a clinically useful parameter for the identification of subjects with a high risk of acute rejection, chronic allograft nephropathy, and graft failure. This simple test could contribute to the prevention of acute rejections and the individualization of immunosuppressive therapies.
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PMID:[Chemokines: possible therapeutic targets and useful clinical parameters in renal transplantation]. 1755 33

Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4(+) BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4(+)VEGFR1(+) hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.
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PMID:The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. 1756 Jan 69

Tumor necrosis factor (TNF)-alpha plays an important role in the mediation of reperfusion-induced tissue injury and lethality. Here, we assessed the effects of PKF242-484 and PKF241-466, two dual inhibitors of TNF-alpha converting enzyme (TACE) and matrix metalloproteinases (MMPs), in a model of ischemia and reperfusion injury in mice. Reperfused animals that received PKF242-484 or PKF241-466 treatment had a dose-dependent reduction of TNF-alpha concentrations in serum. Both drugs delayed and partially inhibited the reperfusion-associated lethality. Maximal inhibition occurred at 10 mg/kg. At this dose, both inhibitors reduced reperfusion-associated local and remote tissue injury, as assessed by changes in vascular permeability, neutrophil recruitment and hemorrhage. In addition, the compounds markedly reduced production of TNF-alpha, CXCL1 (keratinocyte-derived chemokine, KC) and CCL2 (monocyte chemoattractant protein-1, MCP-1) in intestine and lungs of animals which underwent reperfusion. FN-439, an inhibitor of MMPs which possesses no effect on TACE, decreased MMP-2 and MMP-3 activity, but failed to affect tissue injury, TNF-alpha production or lethality. Thus, combined TACE and MMP inhibitors might be effective co-adjuvants in treatments of injuries that follow reperfusion of an ischemic vascular territory. The effects of these drugs on TNF-alpha production appear to be more relevant than their effects on MMP inhibition.
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PMID:Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice. 1761 15


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