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 complement system plays an important role in mediating tissue injury after oxidative stress. The role of mannose-binding lectin (MBL) and the lectin complement pathway (LCP) in mediating complement activation after endothelial oxidative stress was investigated. iC3b deposition on hypoxic (24 hours; 1% O(2))/reoxygenated (3 hours; 21% O(2)) human endothelial cells was attenuated by N-acetyl-D-glucosamine or D-mannose, but not L-mannose, in a dose-dependent manner. Endothelial iC3b deposition after oxidative stress was also attenuated in MBL-deficient serum. Novel, functionally inhibitory, anti-human MBL monoclonal antibodies attenuated MBL-dependent C3 deposition on mannan-coated plates in a dose-dependent manner. Treatment of human serum with anti-MBL monoclonal antibodies inhibited MBL and C3 deposition after endothelial oxidative stress. Consistent with our in vitro findings, C3 and MBL immunostaining throughout the ischemic area at risk increased during rat myocardial reperfusion in vivo. These data suggest that the LCP mediates complement activation after tissue oxidative stress. Inhibition of MBL may represent a novel therapeutic strategy for ischemia/reperfusion injury and other complement-mediated disease states.
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PMID:Complement activation after oxidative stress: role of the lectin complement pathway. 1079 66

Ischemia-reperfusion (I/R) is an important cause of acute renal failure (ARF). The complement system appears to be essentially involved in I/R injury. However, via which pathway the complement system is activated and in particular whether the mannose-binding lectin (MBL)-pathway is activated is unclear. This tempted us to study the activation and regulation of the MBL-pathway in the course of experimental renal I/R injury and in clinical post-transplant ARF. Mice subjected to renal I/R displayed evident renal MBL-depositions, depending on the duration of warm ischemia, in the early reperfusion phase. Renal deposition of C3, C6 and C9 was observed in the later reperfusion phase. The deposition of MBL-A and -C completely co-localized with the late complement factor C6, showing that MBL is involved in complement activation in the course of renal I/R injury. Moreover, the degree of early MBL-deposition correlated with complement activation, neutrophil-influx, and organ-failure observed in the later reperfusion phase. In serum of mice subjected to renal I/R MBL-A, levels increased in contrast to MBL-C levels, which dropped evidently. In line, liver mRNA levels for MBL-A increased, whereas MBL-C levels decreased. Renal MBL mRNA levels rapidly dropped in the course of renal I/R. Finally, in human biopsies, MBL-depositions were observed early after transplantation of ischemically injured kidneys. In line with our experimental data, in ischemically injured grafts displaying post-transplant organ-failure extensive MBL depositions were observed in peritubular capillaries and tubular epithelial cells. In conclusion, in experimental renal I/R injury and clinical post-transplant ARF the MBL-pathway is activated, followed by activation of the complement system. These data indicate that the MBL-pathway is involved in ischemia-induced complement activation.
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PMID:The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury. 1550 37

Reperfusion of ischemic tissues elicits an acute inflammatory response involving serum complement, which is activated by circulating natural IgM specific to self-Ags exposed by ischemia. Recent reports demonstrating a role for the lectin pathway raise a question regarding the initial events in complement activation. To dissect the individual roles of natural IgM and lectin in activation of complement, mice bearing genetic deficiency in early complement, IgM, or mannan-binding lectin were characterized in a mesenteric model of ischemia reperfusion injury. The results reveal that IgM binds initially to ischemic Ag providing a binding site for mannan-binding lectin which subsequently leads to activation of complement and injury.
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PMID:Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. 1698 12

Complement is an important mediator of the injuries observed after skeletal muscle ischemia and subsequent reperfusion. Although the classical pathway had been assumed to be the major pathway of activation leading to injury, the mannose-binding lectin (MBL) pathway might also play a contributing role. In this study, we found that MBL-deficient mice had significant protection after skeletal muscle reperfusion injury compared with wild-type, classical pathway-specific C1q-deficient mice, or MBL-deficient mice reconstituted with recombinant human MBL. MBL-deficient mice, however, were not protected from permeability edema or secondary lung injury after ischemia-reperfusion. These data indicate that blockade of the classical pathway alone (C1q) is protective against permeability edema and remote pulmonary injury but not protective against histologic muscle injury. In contrast, blocking the MBL pathway alone protects against histological injury but is not protective against permeability edema or lung injury. Thus, the activation of both pathways is likely responsible for the full spectrum of injuries observed after skeletal muscle reperfusion injury.
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PMID:The differing roles of the classical and mannose-binding lectin complement pathways in the events following skeletal muscle ischemia-reperfusion. 1711 82

Alternative pathway amplification plays a major role for the final effect of initial specific activation of the classical and lectin complement pathways, but the quantitative role of the amplification is insufficiently investigated. In experimental models of human diseases in which a direct activation of alternative pathway has been assumed, this interpretation needs revision placing a greater role on alternative amplification. We recently documented that the alternative amplification contributed to 80-90% of C5 activation when the initial activation was highly specific for the classical pathway. The recent identification of properdin as a recognition factor directly initiating alternative pathway activation, like C1q in the classical and mannose-binding lectin in the lectin pathway initiates a renewed interest in the reaction mechanisms of complement. Complement and Toll-like receptors, including the CD14 molecule, are two main upstream recognition systems of innate immunity, contributing to the inflammatory reaction in a number of conditions including ischemia-reperfusion injury and sepsis. These systems act as "double-edged swords", being protective against microbial invasion, but harmful to the host when activated improperly or uncontrolled. Combined inhibition of complement and Toll-like receptors/CD14 should be explored as a treatment regimen to reduce the overwhelming damaging inflammatory response during sepsis. The alternative pathway should be particularly considered in this regard, due to its uncontrolled amplification in sepsis. The alternative pathway should be regarded as a dual system, namely a recognition pathway principally similar to the classical and lectin pathways, and an amplification mechanism, well known, but quantitatively probably more important than generally recognized.
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PMID:The alternative complement pathway revisited. 1841 92

Complement activation is initiated by the pattern-recognition molecules complement component C1q, mannose-binding lectin (MBL) and ficolins (H-, L-, M-ficolin), which typically recognize antibody-antigen complexes or foreign polysaccharides. The associated proteases (C1r, C1s, MASP-1 and MASP-2) then activate the complement system. The serpin C1-inhibitor (C1-inh) blocks activity of all these complexes and has been successfully used in models of disease. Many structures of these components became available recently, including that of C1-inh, facilitating the structure-guided design of drugs targeting complement activation. Here, we propose an approach in which therapeutic proteins are made up of natural protein domains and C1-inh to allow targeting to the site of inflammation and more specific inhibition of complement activation. In particular, engineering a fast-acting C1-inh or fusing it to an 'aiming module' has been shown to be feasible and economical using a humanized yeast expression system. Complement-mediated inflammation has been linked to ischemia-reperfusion injury, organ graft rejection and even neurodegeneration, so targeting this process has direct clinical implications.
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PMID:C1, MBL-MASPs and C1-inhibitor: novel approaches for targeting complement-mediated inflammation. 1897 95

Ischemia-reperfusion (I/R) injury provides a substantial limitation to further improvements in the development of therapeutic strategies for ischemia-related diseases. Studies in animal I/R models, including intestinal, hindlimb, kidney, and myocardial I/R models, have established a key role of the complement system in mediation of I/R injury using complement inhibitors and knock-out animal models. As complement activation has been shown to be an early event in I/R injury, inhibiting its activation or its components may offer tissue protection after reperfusion. However, clinical study results using complement inhibitors have largely been disappointing. Therefore, identification of a more specific pathogenic target for therapeutic intervention seems to be warranted. For this purpose more detailed knowledge of the responsible pathway of complement activation in I/R injury is required. Recent evidence from in vitro and in vivo models suggests involvement of both the classic and the lectin pathways in I/R injury via exposition of neo-epitopes in ischemic membranes. However, most of these findings have been obtained in knock-out murine models and have for a large part remained unconfirmed in the human setting. The observation that the relative role of each pathway seems to differ among organs complicates matters further. Whether a defective complement system protects from I/R injury in humans remains largely unknown. Most importantly, involvement of mannose-binding lectin as the main initiator of the lectin pathway has not been demonstrated at tissue level in human I/R injury to date. Thus, conclusions drawn from animal I/R studies should be extrapolated to the human setting with caution.
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PMID:Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies. 1947 97

Complement activation has been shown to play an important role in the inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R). Several recent studies from our laboratory demonstrated the importance of mannose-binding lectin (MBL) as the initiation pathway for complement activation and the resulting pathological effects following MI/R. However, other studies from the past suggest an important role of the classical pathway and perhaps natural antibodies. In the present study, we used newly generated genetically modified mice that lack secreted IgM (sIgM), MBL-A, and MBL-C (sIgM/MBL null) in a plasma reconstitution mouse model of MI/R. Following 30 min of ischemia and 4 h of reperfusion, left ventricular ejection fractions were significantly higher in sIgM/MBL null mice reconstituted with MBL null or sIgM/MBL null plasma compared with reconstitution with wild-type (WT) plasma or WT mice reconstituted with WT plasma following MI/R. Serum troponin I concentration, myocardial polymorphonuclear leukocyte infiltration, and C3 deposition were dependent on the combined presence of sIgM and MBL. These results demonstrate that MI/R-induced complement activation, inflammation, and subsequent tissue injury require both IgM and MBL. Thus MBL-dependent activation of the lectin pathway may not be completely antibody independent in I/R models.
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PMID:Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin. 1974 70

Recent work reveals that the innate immune system is able to recognize self-targets and initiate an inflammatory response similar to that of pathogens. One novel example of this innate autoimmunity is ischemia/reperfusion (I/R) injury, in which reperfusion of the ischemic tissues elicits an acute inflammatory response activated by natural IgM (nIgM) binding to ischemia-specific self-antigens, which are non-muscle myosin heavy chains type II (NMHC-II) subtype A and C. Subsequently, the complement lectin pathway is activated and eventually tissue injury occurs. Although earlier studies in the intestinal model showed that the classical complement pathway did not initiate I/R injury, C1q deposition was still observed in the local injured tissues by imaging analysis. Moreover, the involvement of the alternative complement pathway became unclear due to conflicting reports using different knockout mice. To explore the immediate downstream pathway following nIgM-ischemic antigen interaction, we isolated the nIgM-ischemic antigen immunocomplexes from the local tissue of animals treated in the intestinal I/R injury model, and examined the presence of initial molecules of three complement pathways. Our results showed that mannan-binding lectin (MBL), the early molecule of the lectin pathway, was present in the nIgM-ischemic Ag immunocomplex. In addition, C1q, the initial molecule of the classical pathway was also detected on the immunocomplex. However, Factor B, the early molecule in the alternative pathway, was not detected in the immunocomplex. To further examine the role of the alternative pathway in I/R injury, we utilized Factor B knockout mice in the intestinal model. Our results showed that Factor B knockout mice were not protected from local tissue injury, and their complement system was activated in the local tissues by nIgM during I/R. These results indicated that the lectin complement pathway operates immediately downstream of the nIgM-ischemic antigen interaction during intestinal I/R. Furthermore, the classical complement pathway also appears to interact with the of nIgM-ischemic antigen immunocomplex. Finally, the alternative complement pathway is not involved in I/R injury induction in the current intestinal model.
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PMID:Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury. 2000 73

Vasoocclusive crisis (VOC) is the major cause of morbidity and mortality in sickle cell anemia (SCA), which is caused by the occlusion of blood vessels, followed by ischemia or infarct, resulting in progressive damage to organs. However, this clinical manifestation is variable, indicating that this process could be influenced by modifier genes. The gene MBL2 which codes for mannose-binding lectin (MBL) has been associated with modifications in the progression of infectious and inflammatory vascular diseases. The aim of this study was to determine the frequency of the polymorphisms of exon 1 (alleles A/O) and promoter region -221 (alleles Y/X) of MBL2 in children with SCA and to verify their association with VOC. The determination of the polymorphism of exon 1 and the promoter region of MBL2 was performed by SYBR GREEN((R)) and Taqman((R)) system, respectively. In the patients with SCA, the frequency of the genotype related to high production of MBL was 0.46 (YA/YA) and for intermediate/low production was 0.54 (YA/XA, XA/XA, YA/YO, XA/YO, YO/YO). The frequency of the genotypes and haplotypes of MBL2 in patients with SCA did not differ from control individuals. The populations were in Hardy-Weinberg equilibrium. The patients were divided into two groups. The groups were separated by the frequency of VOC, which was defined by the total of VOC episodes divided by the age of the children at the end of this study. Since, we choose a cut point in FVOC <1 (n=48) (which we considered of mild presentation of disease) and FVOC >or=1 (n=39) (higher severity). In children with SCA, the frequency of the genotypes of MBL2 of intermediate/low expression for MBL was associated with FVOC >or=1 (p=0.0188 OR=3.15 CI=1.19-8.50). The results suggest that MBL2 polymorphism at promoter and first exon of MBL2 associated with low serum levels and structural alterations of MBL could modify the phenotype of the child with SCA related to VOC.
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PMID:Association of variant alleles of MBL2 gene with vasoocclusive crisis in children with sickle cell anemia. 2017 53


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