Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Bustos, Matilde; Coffman, Thomas M.; Saadi, Soheyla; Platt, Jeffrey L.

doi:10.1172/jci119626

Cited by 84 publications

(52 citation statements)

References 33 publications

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“…36 In studies of porcine endothelial cells, exposed to xenoreactive antibodies and complement, IL-1␤ mediated the upregulation of COX-2 and synthesis of PGE 2 and TXA 2 . 37 In studies of neonatal ventricular myocytes, IL-1␤ induced iNOS, COX-2 mRNA, and protein along with a 200-fold increase in PGE 2 . 38 The relationship between the cyclooxygenase and NO pathways varies depending on the circumstances.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of COX-2 During Cardiac Allograft Rejection

Yang

Szabolcs

et al. 2000

Circulation

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Background-The hypothesis that cyclooxygenase-2 (COX-2) is involved in the myocardial inflammatory response during cardiac allograft rejection was investigated using a rat heterotopic abdominal cardiac transplantation model. Methods and Results-COX-2 mRNA and protein in the myocardium of rejecting cardiac allografts were significantly elevated 3 to 5 days after transplantation compared with syngeneic controls (nϭ3, PϽ0.05). COX-2 upregulation paralleled in time and extent the upregulation of iNOS mRNA, protein, and enzyme activity in this model. COX-2 immunostaining was prominent in macrophages infiltrating the rejecting allografts and in damaged cardiac myocytes. Prostaglandin (PG) levels in rejecting allografts were also higher than in native hearts. Because NO has been reported to modulate PG synthesis by COX-2, additional transplants were performed using animals treated with a selective COX-2 inhibitor (SC-58125) and a selective inhibitor of the inducible nitric oxide synthase (iNOS) N-aminomethyl-L-lysine. At posttransplant day 5, inhibitor administration resulted in a significant reduction of COX-2 mRNA expression (3764Ϯ337 versus 5110Ϯ141 arbitrary units, nϭ3, PϽ0.05) and iNOS enzymatic activity (1.7Ϯ0.4 versus 22.8Ϯ14.4 nmol/mg protein, nϭ3, PϽ0.01) compared with vehicle-treated allogeneic transplants. Allograft survival in treated animals was increased modestly from 5.4 to 6.4 days (PϽ0.05). However, apoptosis of cardiac myocytes (TUNNEL method) was only marginally reduced relative to vehicle controls in treated graft recipients. The intensity of allograft rejection was also similar in the treated and untreated allografts. Conclusions-The data indicates that COX-2 expression is enhanced in parallel with iNOS in the myocardium during cardiac allograft rejection. (Circulation. 2000;101:430-438.)

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Section: Discussionmentioning

confidence: 99%

Upregulation of COX-2 During Cardiac Allograft Rejection

Yang

Szabolcs

et al. 2000

Circulation

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“…Both anaphylatoxins and MAC may have contributed to the endothelial injury and activation after IR in the CD55 Ϫ/Ϫ CD59 Ϫ/Ϫ mice. Apart from direct loss of function associated with necrotic injury, activated endothelial cells may increase adhesion molecule expression and produce inflammatory cytokines and lipid mediators (32,33). Such events may create medullary vascular congestion and accumulation of intravascular leukocytes.…”

Section: Discussionmentioning

confidence: 99%

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Yamada

Miwa

Liu

et al. 2004

The Journal of Immunology

153

135

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Renal ischemia-reperfusion injury (IRI) is a feature of ischemic acute renal failure and it impacts both short- and long-term graft survival after kidney transplantation. Complement activation has been implicated in renal IRI, but its mechanism of action is uncertain and the determinants of complement activation during IRI remain poorly understood. We engineered mice deficient in two membrane complement regulatory proteins, CD55 and CD59, and used them to investigate the role of these endogenous complement inhibitors in renal IRI. CD55-deficient (CD55−/−), but not CD59-deficient (CD59−/−), mice exhibited increased renal IRI as indicated by significantly elevated blood urea nitrogen levels, histological scores, and neutrophil infiltration. Remarkably, although CD59 deficiency alone was inconsequential, CD55/CD59 double deficiency greatly exacerbated IRI. Severe IRI in CD55−/−CD59−/− mice was accompanied by endothelial deposition of C3 and the membrane attack complex (MAC) and medullary capillary thrombosis. Complement depletion in CD55−/−CD59−/− mice with cobra venom factor prevented these effects. Thus, CD55 and CD59 act synergistically to inhibit complement-mediated renal IRI, and abrogation of their function leads to MAC-induced microvascular injury and dysfunction that may exacerbate the initial ischemic assault. Our findings suggest a rationale for anti-complement therapies aimed at preventing microvascular injury during ischemia reperfusion, and the CD55−/−CD59−/− mouse provides a useful animal model in this regard.

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“…24,25 Similarly, platelets may affect polymorphonuclear cell activation by release of thromboxane A2, platelet derived growth factor, serotonin, lipooxygenase products, proteases and adenosine. Finally, interaction between endothelium, platelets and polymorphonuclear cells can induce noreflow, even if no thrombosis occurred.…”

Section: (Iv) Inflammationmentioning

confidence: 99%

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

Kang

Yang

2007

CIM

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Purpose: To review (1) the mechanisms of coronary microvascular reperfusion injury, particularly in the relationships between microvascular endothelium dysfunction, microstructure damage, microemboli and no-reflow phenomena; (2) the no-reflow presentation and management at ischemia-reperfusion to suggest future direction for noreflow therapy in acute myocardial infarction. Sources: Original articles and reviews published between 1997 and 2007 and focusing on the no-reflow phenomenon in MEDLINE and PubMed. The search terms used were "no-reflow", "microvascular injury", "acute myocardial infarction" and "reperfusion injury". All papers identified were English-language, full text papers. In addition, the reference lists of identified relevant articles were also searched. Conclusions:The no-reflow phenomenon is characterised by damage to microvascular function and microstructure at ischaemia-reperfusion. Microemboli contribute to noreflow. Clinical myocardial contrast echocardiography (MCE), scintigraphic and magnetic resonance imaging (MRI) have shown evidence of microvascular damage, eg, perfusion defects are closely related to lack of contractile recovery and irreversible myocyte damage. Clinical agents and devices targeting microvascular injury (especially protection of endothelium and reduction of microemboli) after acute myocardial infarction may be key points to improve no-reflow.

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Modulation of eicosanoid metabolism in endothelial cells in a xenograft model. Role of cyclooxygenase-2.

Cited by 84 publications

References 33 publications

Upregulation of COX-2 During Cardiac Allograft Rejection

Upregulation of COX-2 During Cardiac Allograft Rejection

Critical Protection from Renal Ischemia Reperfusion Injury by CD55 and CD59

Coronary microvascular reperfusion injury and no-reflow in acute myocardial infarction

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