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)

The effects of hypoxia-ischemia (HI) on proliferation and differentiation in the immature (postnatal day 9) and juvenile (postnatal day 21) mouse hippocampus were investigated by injecting bromodeoxyuridine (50 mg/kg) daily for 7 days after the insult and evaluating the labeling 5 weeks after HI. Phenotypic differentiation was evaluated using NeuN, Iba1, APC, and S100beta as markers of neurons, microglia, oligodendrocytes, and astrocytes, respectively. The basal proliferation, in particular neurogenesis, was higher in the immature than in the juvenile hippocampus. Hypoxia-ischemia did not increase neurogenesis significantly in the immature dentate gyrus (DG), but it increased several-fold in the juvenile brain, reaching the same level as in the normal, noninjured immature brain. This suggests that the immature hippocampus is already working at the top of its proliferative capacity and that even though basal neurogenesis decreased with age, the injury-induced generation of new neurons in the juvenile hippocampus could not increase beyond the basal level of the immature brain. Generation of glial cells of all three types after HI was significantly more pronounced in the cornu ammonis of the hippocampus region of the juvenile hippocampus. In the DG, only microglia production was greater in the juvenile brain. Increased microglia proliferation correlated with increased levels of the proinflammatory cytokines MCP-1 and IL-18 3 days after HI, indicating that the inflammatory response is stronger in the juvenile hippocampus. In summary, contrary to what has been generally assumed, our results indicate that the juvenile brain has a greater capacity for neurogenesis after injury than the immature brain.
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PMID:Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia. 1692 44

Acute renal failure often occurs in the clinical setting of multiple renal insults. Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of cisplatin nephrotoxicity, ischemia-reperfusion injury, and endotoxin-induced acute renal failure. The current studies examined the interactions between cisplatin and endotoxin with particular emphasis on TNF-alpha production. Treatment of cultured murine proximal tubule cells (TKPTS cells) with cisplatin resulted in a modest production of TNF-alpha, while treatment with endotoxin did not result in any TNF-alpha production. However, the combination of cisplatin and endotoxin resulted in large amounts of TNF-alpha synthesis and secretion. The stimulation of TNF-alpha production was dependent on cisplatin-induced activation of p38 MAPK and was associated with phosphorylation of the translation initiation factor eIF4E and its upstream kinase Mnk1. Inhibition of p38 MAPK and, to a lesser extent, ERK, reduced cisplatin+endotoxin-stimulated TNF-alpha production and phosphorylation of Mnk1 and eIF4E. Synergy between cisplatin and endotoxin was also observed in certain tumor cell lines, but not in macrophages. In macrophages, in contrast to TKPTS cells, endotoxin alone activated p38 MAPK and stimulated TNF-alpha production with no added impact by cisplatin. The combination of cisplatin and endotoxin did not result in synergistic production of other cytokines, e.g., MCP-1 and MIP2, by TKPTS cells. In summary, these studies indicate that cisplatin sensitizes renal epithelial cells to endotoxin and dramatically increases the translation of TNF-alpha mRNA in a p38 MAPK-dependent manner. These interactions between cisplatin and endotoxin may be relevant to the pathogenesis of cisplatin nephrotoxicity in humans.
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PMID:Endotoxin and cisplatin synergistically stimulate TNF-alpha production by renal epithelial cells. 1703 36

Bradykinin B1 receptors are exclusively expressed in inflamed tissues. For this reason, they have been related with the outcomes of several pathologies. Ischemia-reperfusion injury is caused by the activation of inflammatory and cytoprotective genes, such as macrophage chemoattractant protein-1 and heme oxygenase-1, respectively. This study was aimed to analyze the involvement of bradykinin B1 and B2 receptors (B1R and B2R) in tissue response after renal ischemia-reperfusion injury. For that, B1R (B1-/-), B2R (B2-/-) knockout animals and its control (wild-type mice, B1B2+/+) were subjected to renal bilateral ischemia, followed by 24, 48 and 120 h of reperfusion. At these time points, blood serum samples were collected for creatinine and urea dosages. Kidneys were harvested for histology and molecular analyses by real-time PCR. At 24 and 48 h of reperfusion, B1-/- group resulted in the lowest serum creatinine and urea levels, indicating less renal damage, which was proved by renal histology. Renal protection associated with B1-/- mice was also related with higher expression of HO-1 and lower expression of MCP-1. In conclusion, the absence of B1R had a protective role against inflammatory responses developed after renal ischemia-reperfusion injury.
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PMID:Influence of bradykinin B1 and B2 receptors in the immune response triggered by renal ischemia-reperfusion injury. 1716 49

Normal kidneys regenerate after acute injury with little development of chronic fibrosis. However, the long-term effects of an acute injury in kidneys with established chronic toxicity induced by cyclosporine (CsA) are not entirely clear. To study the consequences of an ischemia and reperfusion (IR) injury in long-term CsA-treated rats, male Wistar rats (250-300 g) were treated daily with CsA (10 mg/kg) or vehicle (olive oil 1 mL/kg) for 28 days. On day 21, ischemia was performed by clamping the renal vessel for 1 hour. Blood samples were collected on days 0 and 21 (before IR) as well as days 22 and 28. On day 28, the kidneys were collected to examine the mRNA expression of MCP-1 by real-time PCR. For renal function, serum creatinine levels were measured. Twenty-four hours after reperfusion, long-term CsA-treated animals showed better renal function compared with the control group, as demonstrated by serum creatinine levels: 2.2 +/- 0.13 mg/dL vs 2.9 +/- 0.18 mg/dL, respectively (P < .05). However, 1 week after IR, the renal function was worse among the long-term CsA-treated group than the controls: 1.16 +/- 0.08 mg/dL vs 0.8 +/- 0.09 mg/dL, respectively (P < .05). Interestingly, CsA treatment was associated with lower MCP-1 mRNA expression than that in the control group: mean MCP-1 mRNA expression 0.58 +/- 0.13 vs 1.02 +/- 0.12, respectively (P < .05). In conclusion, animals with chronic CsA nephrotoxicity were protected from an acute renal injury, possibly through decreased chemokine production, although at later time points, renal function was clearly impaired, probably by the acceleration of vasculopathy caused by nephrotoxicity.
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PMID:Dual response of animals with chronic cyclosporine nephrotoxicity to an acute ischemic injury. 1717 67

Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. The mechanism(s) by which acute and chronic myocardial ischemia translate into the characteristic features of ischemic cardiomyopathy is unresolved at present. We hypothesized that such translation relates to modification of specific gene expression programs during acute and chronic ischemic insults to the myocardium. Global mRNA expression profiles by Affymetrix HG_U133A GeneChip analysis on 33 samples was performed on non-failing human left ventricular myocardium during acute and chronic ischemia in 6 patients undergoing coronary artery by-pass grafting. Results were confirmed by real-time quantitative RT-PCR in 14 patients and supported by histology and immunohistochemistry analyses. Acute ischemia elicited an acute inflammatory response including IL-6, IL-8, MCP-1, VCAM-1 and CYR-61 with an attenuated increase of IL-6 and IL-8 in chronic ischemic myocardium compared to normal myocardium. High mRNA expression of connective tissue growth factor (CTGF) was present in chronic ischemic myocardium with a high degree of correlation between CTGF and mRNA expression of specific genes (e.g. thrombospondin 4, collagen type Ialpha2, versican, adlican, latent transforming growth factor beta binding protein 2 and fibronectin) involved in extracellular matrix remodelling. In conclusion, acute inflammatory induction (e.g. IL-8, IL-6, VCAM-1 and MCP-1) and an acute phase CCN family gene with effects on matrix interactions (CYR-61) might play important roles in the coupling between acute ischemic episodes and chronic myocardial remodelling. In addition, the findings support an important role of CTGF signalling in chronic extracellular matrix remodelling in chronic coronary artery disease.
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PMID:Gene expression signals involved in ischemic injury, extracellular matrix composition and fibrosis defined by global mRNA profiling of the human left ventricular myocardium. 1734 75

Gut manipulation and ischemia/reperfusion evoke an inflammatory response within the intestinal muscularis that contributes to dysmotility. We hypothesize that resident macrophages play a key role in initiating the inflammatory cascade. Isogenic small bowel transplantation was performed in Lewis rats. The impact of recovery of organs on muscularis inflammation was investigated by comparing cold whole-body perfusion after versus prior to recovery. The role of macrophages was investigated by transplantation of macrophage-depleted gut. Leukocytes were counted using muscularis whole mounts. Mediator expression was determined by real-time RT-PCR. Contractility was assessed in a standard organ bath. Both organ recovery and ischemia/reperfusion induced leukocyte recruitment and a significant upregulation in IL-6, MCP-1, ICAM-1 and iNOS mRNAs. Although organ recovery in cold ischemia prevented early gene expression, peak expression was not changed by modification of the recovery technique. Compared to controls, transplanted animals showed a 65% decrease in smooth muscle contractility. In contrast, transplanted macrophage-depleted isografts exhibited significant less leukocyte infiltration and only a 19% decrease in contractile activity. In summary, intestinal manipulation during recovery of organs initiates a functionally relevant inflammatory response within the intestinal muscularis that is massively intensified by the ischemia reperfusion injury. Resident muscularis macrophages participate in initiating this inflammatory response.
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PMID:Resident macrophages are involved in intestinal transplantation-associated inflammation and motoric dysfunction of the graft muscularis. 1735 14

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

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

Endogenous mechanisms exist to limit inflammation. One such molecule is netrin. This study examined the impact of ischemia-reperfusion (I/R) on netrin expression and the role of netrin in preventing renal inflammation and injury. All three isoforms of netrin (1, 3, and 4) are expressed in normal kidney. I/R significantly downregulated netrin-1 and -4 mRNA expression, whereas expression of netrin-3 was moderately upregulated at 24 h of reperfusion. The netrin receptor UNC5B mRNA increased at 3 h and but decreased at later time points. Expression of a second netrin receptor, DCC, was not altered significantly. I/R was associated with dramatic changes in netrin-1 protein abundance and localization. Netrin-1 protein levels increased between 3 and 24 h after reperfusion. Immunolocalization showed an interstitial distribution of netrin-1 in sham-operated kidneys which colocalized with Von Willebrand Factor suggesting the presence of netrin-1 in peritubular capillaries. After I/R, interstitial netrin-1 expression decreased and netrin-1 appeared in tubular epithelial cells. By 72 h after reperfusion, netrin-1 reappeared in the interstitium while tubular epithelial staining decreased significantly. Downregulation of netrin-1 in the interstitium corresponded with increased MCP-1 and IL-6 expression and infiltration of leukocytes into the reperfused kidney. Administration of recombinant netrin-1 significantly improved kidney function (blood urea nitrogen: 161 +/- 7 vs. 104 +/- 24 mg/dl, creatinine: 1.3 +/- 0.07 vs. 0.75 +/- 0.16 mg/dl, P < 0.05 at 24 h) and reduced tubular damage and leukocyte infiltration in the outer medulla. These results suggest that downregulation of netrin-1 in vascular endothelial cells may promote endothelial cell activation and infiltration of leukocytes into the kidney thereby enhancing tubular injury.
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PMID:Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney. 1821 45

Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by excessive extracellular matrix deposition and vascular injury in the skin and internal organs. Although the pathogenesis remains unclear, Raynaud's phenomenon, a kind of ischemia-reperfusion, usually precedes the development of skin sclerosis. Therefore, it is possible that endothelial cell injury caused by recurring ischemia-reperfusion induces inflammatory cell infiltration and subsequent cytokine production, leading to the development of tissue fibrosis. During this process, chemokines likely have important roles via mediating chemotaxis and activation of leukocytes, result in the interaction between leukocytes and fibroblasts. While chemokine abnormalities of SSc have been reported in amounts of literatures, monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, CCR2, likely have the most critical role for the development of SSc. Here recent data will be reviewed on the potential role of chemokines and their receptors in SSc.
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PMID:The roles of chemokines in the development of systemic sclerosis. 1831 Oct 40


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