Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury.

Crawford, Michael H.; Grover, Fred; Kolb, William P.; McMahan, C. Alex; O’Rourke, Robert A.; McManus, Linda M.; Pinckard, R. N.

doi:10.1161/01.cir.78.6.1449

Cited by 155 publications

(73 citation statements)

References 24 publications

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“…Infiltration of the heart by PMNs is an important cause of myocardial damage in the setting of ischemia/reperfusion (47)(48)(49)(50)(51)(52)(53). Consistent with this view, histologic examination of the vasculature from a heart preserved in LR, which subsequently failed, showed a ring of PMNs adherent to the vessel surface, which was not seen in a successfully transplanted cardiac graft preserved in LR + db-cAMP (Fig.…”

Section: Resultsmentioning

confidence: 56%

Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model.

Pinsky

Öz²,

Liao³

et al. 1993

J. Clin. Invest.

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Current organ preservation strategies subject graft vasculature to severe hypoxia (Po2 -20 Torr), potentially compromising vascular function and limiting successful transplantation. Previous work has shown that cAMP modulates endothelial cell (EC) antithrombogenicity, barrier function, and leukocyte /EC interactions, and that hypoxia suppresses EC cAMP levels. To explore the possible benefits of cAMP analogs/agonists in organ preservation, we used a rat heterotopic cardiac transplant model; dibutyryl cAMP added to preservation solutions was associated with a time-and dose-dependent increase in the duration of cold storage associated with successful graft function.Preservation was also enhanced by 8-bromo-cAMP, the SP isomer of adenosine 3',5'monophosphorothioate, and types III (indolidan) and IV (rolipram) phosphodiesterase inhibitors. Neither butyrate alone nor 8-bromoadenosine were effective, and the cAMP-dependent protein kinase antagonist Rp isomer of adenosine 3',5'monophosphorothioate prevented preservation enhancement induced by 8-bromo-cAMP. Grafts stored with dibutyryl cAMP demonstrated a 5.5-fold increase in blood flow and a 3.2-fold decreased neutrophil infiltration after transplantation. To explore the role of cAMP in another cell type critical for vascular homeostasis, vascular smooth muscle cells were subjected to hypoxia, causing a time-dependent decline in cAMP levels. Although adenylate cyclase activity was unchanged, diminished oxygen tensions were associated with enhanced phosphodiesterase activity (59 and 30% increase in soluble types III and IV activity, respectively). These data suggest that hypoxia or graft ischemia disrupt vascular homeostasis, at least in part, by perturbing the cAMP second messenger pathway. Supplementation of this pathway provides a new approach for enhancing cardiac preservation, promoting myocardial function, and maintaining vascular homeostatic properties. (J.

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Section: Resultsmentioning

confidence: 56%

Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model.

Pinsky

Öz²,

Liao³

et al. 1993

J. Clin. Invest.

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“…Finally, complement activation may additionally be driven by other processes such as reperfusion events [42][43][44][45] or liberation of intracellular complement activators from the cells. 46,47 A major unanswered question relates to the problem of why the terminal complement sequence should assume such a central role in atherogenesis. It is possible that C5b-9 attack on nucleated cells occurs at some stage, accentuating proin- Immunostaining of aortic cross sections using a monoclonal antibody directed against rabbit C5b-9.…”

Section: Discussionmentioning

confidence: 99%

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

Schmiedt

Kinscherf

Deigner

et al. 1998

ATVB

120

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Abstract-Low-density lipoprotein (LDL) can be transformed to an atherogenic moiety by nonoxidative, enzymatic degradation. Enzymatically degraded LDL induces macrophage foam cell formation, provokes release of cytokines, and also activates complement. To determine whether complement activation may contribute to atherogenesis, 6 pairs of homozygous C6-deficient rabbits and their non-C6-deficient heterozygous siblings were fed a cholesterol-rich diet for 14 weeks. Cholesterol levels and plasma lipoprotein profiles of the animals in the C6-competent and C6-deficient groups did not significantly differ, and the high density lipoprotein and LDL cholesterol ratios at the end of the experiment were 0.07Ϯ0.01 and 0.08Ϯ0.01 (SEM), respectively. However, differences in atherosclerotic plaque formation were discernible macroscopically, with extensive aortic lesions being visible in all C6-competent animals and absent in all C6-deficient animals. Aortas were sectioned from thorax to abdomen, and 10 sections were stained from each aorta. Quantification of atherosclerotic lesions and lumen stenosis with the use of computer-based morphometry documented a dramatic protective effect of C6 deficiency on the development of diet-induced atherosclerosis. We conclude that the terminal complement sequence is centrally involved in atherosclerotic lesion progression. (Arterioscler Thromb Vasc Biol. 1998;18:1790-1795.)Key Words: complement activation Ⅲ atherosclerosis T he possible relevance of complement activation in atherogenesis has not received much attention to date, and only a few reviews are available on the topic. 1,2 The first immunohistochemical studies on complement deposition in atherosclerotic lesions appeared in 1985 to 1987, 3-5 and C5b-9 complexes were subsequently quantified by ELISA in detergent extracts of lesion homogenates. 6 In those studies, the stages of lesion development were not defined, so it could not be excluded that complement activation might have occurred subsequent to tissue damage. An experimental study was then performed in rabbits, leading to the clear demonstration that diet-induced deposition of lipids in the subendothelium was temporally associated with complement activation, which occurred before lesion infiltration by monocytes. 7 A directed search led to tentative identification of the complement-activating entity. Heterogeneously sized lipid droplets containing high amounts of free cholesterol were isolated from early lesions and were shown to be capable of spontaneously activating the alternative complement pathway. 8 The origin of this lipid, termed the lesion complement activator (LCA), was unknown, but the possibility that it represented an LDL derivative was obvious. To corroborate this assumption, attempts were undertaken to transform LDL in vitro into a complement-activating moiety. This was found to be possible by combined treatment of the lipoprotein with a protease, cholesterol-esterase, and neuraminidase, 9 enzymes that occur ubiquitously in lysosomes of mammalian cells and that are...

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“…Organ ischemia induces immediate cellular injury that is significantly magnified by the return of blood flow and can lead to a systemic inflammatory response that damages remote organs as well (1). Due to the sensitivity of the mucosal surfaces, ischemia/reperfusion (I/R) 3 -induced injury is exceptionally prominent in the intestine and is frequently followed by liver and lung damage (2).…”

mentioning

confidence: 99%

“…Mesenteric I/R-induced tissue injury is mediated by at least two components, neutrophil infiltration and complement activation (3)(4)(5). Initial studies showed protection from I/R-induced injury after neutrophil depletion (4,5).…”

mentioning

confidence: 99%

Anti-Phospholipid Antibodies Restore Mesenteric Ischemia/Reperfusion-Induced Injury in Complement Receptor 2/Complement Receptor 1-Deficient Mice

Fleming

Egan

Chai

et al. 2004

The Journal of Immunology

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Complement receptor 2-deficient (Cr2−/−) mice are resistant to mesenteric ischemia/reperfusion (I/R) injury because they lack a component of the natural Ab repertoire. Neither the nature of the Abs that are involved in I/R injury nor the composition of the target Ag, to which recognition is lacking in Cr2−/− mice, is known. Because anti-phospholipid Abs have been shown to mediate fetal growth retardation and loss when injected into pregnant mice, we performed experiments to determine whether anti-phospholipid Abs can also reconstitute I/R injury and, therefore, represent members of the injury-inducing repertoire that is missing in Cr2−/− mice. We demonstrate that both murine and human monoclonal and polyclonal Abs against negatively charged phospholipids can reconstitute mesenteric I/R-induced intestinal and lung tissue damage in Cr2−/− mice. In addition, Abs against β2 glycoprotein I restore local and remote tissue damage in the Cr2−/− mice. Unlike Cr2−/− mice, reconstitution of I/R tissue damage in the injury-resistant Rag-1−/− mouse required the infusion of both anti-β2-glycoprotein I and anti-phospholipid Ab. We conclude that anti-phospholipid Abs can bind to tissues subjected to I/R insult and mediate tissue damage.

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Complement and neutrophil activation in the pathogenesis of ischemic myocardial injury.

Cited by 155 publications

References 24 publications

Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model.

Restoration of the cAMP second messenger pathway enhances cardiac preservation for transplantation in a heterotopic rat model.

Complement C6 Deficiency Protects Against Diet-Induced Atherosclerosis in Rabbits

Anti-Phospholipid Antibodies Restore Mesenteric Ischemia/Reperfusion-Induced Injury in Complement Receptor 2/Complement Receptor 1-Deficient Mice

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