Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction.

Pinckard, R. N.; Olson, Merle S.; Giclas, Patricia C.; Terry, Raya D.; Boyer, John T.; O’Rourke, Robert A.

doi:10.1172/jci108145

Cited by 179 publications

(71 citation statements)

References 16 publications

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“…It is important to note that, regardless of the mechanism which leads to their production, the complement-derived anaphylatoxins generated in the plasma of patients with active SLE are potential inflammatory mediators: C3a des Arg and C5a desArg activate platelets (29) and neutrophils (30), respectively. Aggregation of these cells in small vessels following exposure to C3a desArg and C5a desArg has been invoked as a cause of vascular injury in diverse clinical syndromes including the adult respiratory distress syndrome (3 l), cerebral injury following extracorporeal circulation (32,33), reperfusion injury of the myocardium (34,35), and endotoxic shock (36). We have recently provided serologic and histologic evidence which suggests that syndromes of reversible hypoxemia and cerebritis in SLE may have a similar pathogenic mechanism (37).…”

Section: Discussionmentioning

confidence: 99%

Up‐Regulation of Endothelial Cell Adhesion Molecules Characterizes Disease Activity in Systemic Lupus Erythematosus

Hm¹,

Buyon²,

Giorno³

et al. 1994

Arthritis & Rheumatism

163

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Objective. To test the hypothesis that during exacerbations of systemic lupus erythematosus (SLE), endothelial cells are activated to increase their expression of adhesion molecules.Methods. Endothelial cell expression of E-selectin, vascular cell adhesion molecule 1 (VCAM-l), and intercellular adhesion molecule 1 (ICAM-1) was quantitated immunohistochemically in 20 biopsy specimens from nonlesional, non-sun-exposed skin from 16 SLE patients. Disease activity was evaluated with the SLE Disease Activity Index (SLEDAI) and with measurements of complement components C3a desArg, C3, and C4.Results. The mean expression of all 3 adhesion molecules was significantly elevated in patients with SLE versus healthy controls, as well as in patients with active versus inactive SLE. The mean C3a desArg level was significantly higher in patients with active SLE compared with those with inactive SLE. The SLEDAI scores correlated directly with C3a desArg levels and inversely with C3 and with C4 levels. Evaluation of serial biopsy specimens demonstrated loss of endothelial cell adhesion molecules and reduction of C3a levels with clinical improvement .

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Section: Discussionmentioning

confidence: 99%

Up‐Regulation of Endothelial Cell Adhesion Molecules Characterizes Disease Activity in Systemic Lupus Erythematosus

Hm¹,

Buyon²,

Giorno³

et al. 1994

Arthritis & Rheumatism

163

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“…Hill and Ward [27] were the first to demonstrate that leukotactic activity in rat myocardial infarcts was in part due to C3 cleavage products. Subsequently Pinckard and colleagues [28] showed evidence of C1, C3 and C4 consumption in patients with acute myocardial infarction, suggesting that myocardial cell necrosis results in the release of subcellular membrane constituents capable of activating the complement cascade. Further studies [26,29] have suggested that during myocardial ischemia, mitochondria, extruded through breaks in the sarcolemma, unfold and release membrane fragments rich in cardiolipin and protein.…”

Section: The Complement Cascadementioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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“…Giclas and colleagues showed many years ago that mitochondria can activate the complement cascade, thereby contributing to the proinflammatory effects of lysed cells (10,11). Future work will focus on the effects of serum in our in vitro system and how it influences the interaction between apoptotic cells and macrophages; however, preliminary data suggest that exposing macrophages to either apoptotic neutrophils or Jurkat T cells in the presence of serum still causes down-regulation of TNF-␣ and chemokine production, as is seen in the absence of serum; TGF-␤ production is also up-regulated (V.A.F., unpublished data).…”

Section: Figurementioning

confidence: 99%

“…Therefore, we compared the direct effects of binding and/or uptake of apoptotic vs lysed neutrophils and lymphocytes on cytokine production by unstimulated or zymosan-stimulated macrophages. The experiments were performed in the absence of serum to rule out the potential contribution of complement fixation following exposure to intracellular organelles (10,11).…”

mentioning

confidence: 99%

Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases

Fadok

Bratton

Guthrie

et al. 2001

The Journal of Immunology

338

284

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Granulocytes undergoing apoptosis are recognized and removed by phagocytes before their lysis. The release of their formidable arsenal of proteases and other toxic intracellular contents into tissues can create significant damage, prolonging the inflammatory response. Binding and/or uptake of apoptotic cells by macrophages inhibits release of proinflammatory cytokines by mechanisms that involve anti-inflammatory mediators, including TGF-β. To model the direct effects of necrotic cells on macrophage cytokine production, we added lysed or apoptotic neutrophils and lymphocytes to mouse and human macrophages in the absence of serum to avoid complement activation. The results confirmed the ability of lysed neutrophils, but not lymphocytes, to significantly stimulate production of macrophage-inflammatory protein 2 or IL-8, TNF-α, and IL-10. Concomitantly, induction of TGF-β1 by lysed neutrophils was significantly lower than that observed for apoptotic cells. The addition of selected serine protease inhibitors and anti-human elastase Ab markedly reduced the proinflammatory effects, the lysed neutrophils then behaving as an anti-inflammatory stimulus similar to intact apoptotic cells. Separation of lysed neutrophils into membrane and soluble fractions showed that the neutrophil membranes behaved like apoptotic cells. Thus, the cytokine response seen when macrophages were exposed to lysed neutrophils was largely due to liberated proteases. Therefore, we suggest that anti-inflammatory signals can be given by PtdSer-containing cell membranes, whether from early apoptotic, late apoptotic, or lysed cells, but can be overcome by proteases liberated during lysis. Therefore, the outcome of an inflammatory reaction and the potential immunogenicity of Ags within the damaged cell will be determined by which signals predominate.

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Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction.

Cited by 179 publications

References 16 publications

Up‐Regulation of Endothelial Cell Adhesion Molecules Characterizes Disease Activity in Systemic Lupus Erythematosus

Up‐Regulation of Endothelial Cell Adhesion Molecules Characterizes Disease Activity in Systemic Lupus Erythematosus

The immune system and cardiac repair

Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases

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