C5a-induced expression of P-selectin in endothelial cells.

Foreman, Kimberly E.; Vaporciyan, Ara A.; Bonish, Brian K.; Jones, Michael L.; Johnson, Kent J.; Glovsky, M. Michael; Eddy, Susan; Ward, Peter A.

doi:10.1172/jci117430

Cited by 440 publications

(298 citation statements)

References 43 publications

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“…Although many other inflammatory pathways can lead to neutrophil priming and chemotaxis, virtually no neutrophils were seen in the fB Ϫ/Ϫ group, demonstrating that these other pathways are not playing a significant role in neutrophil recruitment in this model. Complement activation has been shown to increase expression of the adhesion molecules P-selectin, Eselectin, and ICAM-1 (31,32). By increasing expression of these adhesion molecules, complement activation may initiate neutrophil infiltration.…”

Section: Discussionmentioning

confidence: 99%

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Thurman

Ljubanović

Edelstein

et al. 2003

The Journal of Immunology

249

231

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Ischemia/reperfusion (I/R) injury of the kidney is a common cause of acute renal failure (ARF) and is associated with high morbidity and mortality in the intensive care unit. The mechanisms underlying I/R injury are complex. Studies have shown that complement activation contributes to the pathogenesis of I/R injury in the kidney, but the exact mechanisms of complement activation have not been defined. We hypothesized that complement activation in this setting occurs via the alternative pathway and that mice deficient in complement factor B, an essential component of the alternative pathway, would be protected from ischemic ARF. Wild-type mice suffered from a decline in renal function and had significant tubular injury, particularly in the outer medulla, after I/R. We found that factor B-deficient mice (fB−/−) developed substantially less functional and morphologic renal injury after I/R. Furthermore, control wild-type mice had an increase in tubulointerstitial complement C3 deposition and neutrophil infiltration in the outer medulla after I/R, whereas fB−/− mice demonstrated virtually no C3 deposition or neutrophil infiltration. Our results demonstrate that complement activation in the kidney after I/R occurs exclusively via the alternative pathway, and that selective inhibition of this pathway provides protection to the kidneys from ischemic ARF.

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Section: Discussionmentioning

confidence: 99%

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Thurman

Ljubanović

Edelstein

et al. 2003

The Journal of Immunology

249

231

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“…This injury has been attributed to biological effects of C5a and MAC. C5aR has been localized by immunohistology on bronchial and alveolar epithelial cells as well as vascular smooth muscle and endothelial cells of human lung tissue (26,28,57,58). The potential for tissue activation through the C5aR has been verified for endothelial cells in culture.…”

Section: Figurementioning

confidence: 98%

“…The potential for tissue activation through the C5aR has been verified for endothelial cells in culture. Foreman and colleagues (28) found that C5a could activate endothelial cells directly through C5aR and that this activation was augmented in the presence of TNF-␣. Using C5aR knockout mice, Hopken et al (59) have demonstrated a dominant role for the C5aR in the lung, but only a synergistic role together with other inflammatory mediators in immune complex-mediated peritonitis and skin injury.…”

Section: Figurementioning

confidence: 99%

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Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection

Nakashima

Qian

Rahimi

et al. 2002

The Journal of Immunology

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The lung is known to be particularly susceptible to complement-mediated injury. Both C5a and the membrane attack complex (MAC), which is formed by the terminal components of complement (C5b-C9), can cause acute pulmonary distress in nontransplanted lungs. We used C6-deficient rats to investigate whether MAC causes injury to lung allografts. PVG.R8 lungs were transplanted orthotopically to MHC class I-incompatible PVG.1U recipients. Allografts from C6-sufficient (C6+) donors to C6+ recipients were rejected with an intense vascular infiltration and diffuse alveolar hemorrhage 7 days after transplantation (n = 5). Ab and complement (C3d) deposition was accompanied by extensive vascular endothelial injury and intravascular release of von Willebrand factor. In contrast, lung allografts from C6-deficient (C6−) donors to C6− recipients survived 13–17 days (n = 5). In the absence of C6, perivascular mononuclear infiltrates of ED1+ macrophages and CD8+ T lymphocytes were present 7 days after transplantation, but vascular endothelial cells were quiescent, with minimal von Willebrand factor release and no evidence of alveolar hemorrhage or edema. Lung allografts were performed from C6− donors to C6+ recipients (n = 5) and from C6+ donors to C6− recipients (n = 5) to separate the effects of systemic and local C6 production. Lungs transplanted from C6+ donors to C6− recipients had increased alveolar macrophages and capillary injury. C6 production by lung allografts was demonstrated at the mRNA and protein levels. These results demonstrate that MAC causes vascular injury in lung allografts and that the location of injury is dependent on the source of C6.

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“…These two receptors belong to the seven-transmembrane receptor superfamily and are coupled to a G i protein (2,3). C3aR and C5aR are expressed in myeloid cells (4 -8) and, more surprisingly, in non-myeloid cells and tissues (7)(8)(9)(10). In the central nervous system it has been shown that C3aR and C5aR are constitutively expressed by glial cells in vitro (11)(12)(13)(14) and in vivo (15) and that the expression of C3aR and C5aR is increased in inflammatory conditions (15)(16)(17).…”

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confidence: 99%

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

Bénard

Gonzalez

Schouft

et al. 2004

Journal of Biological Chemistry

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There is now clear evidence that the Complement anaphylatoxin C3a and C5a receptors (C3aR and C5aR) are expressed in glial cells, notably in astrocytes and microglia. In contrast, very few data are available concerning the possible expression of these receptors in neurons. Here, we show that transient expression of C3aR and C5aR occurs in cerebellar granule neurons in vivo with a maximal density in 12-day-old rat, suggesting a role of these receptors during development of the cerebellum. Expression of C3aR and C5aR mRNAs and proteins was also observed in vitro in cultured cerebellar granule cells. Quantification of the mRNAs by real-time reverse transcription-PCR showed a peak of expression at day 2 in vitro (DIV 2); the C3aR and C5aR proteins were detected by Western blot analysis at DIV 4 and by flow cytometry and immunocytochemistry in differentiating neurons with a maximum density at DIV 4 -9. Apoptosis of granule cells plays a crucial role for the harmonious development of the cerebellar cortex. We found that, in cultured granule neurons in which apoptosis was induced by serum deprivation and low potassium concentration, a C5aR agonist promoted cell survival and inhibited caspase-3 activation and DNA fragmentation. The neuroprotective effect of the C5aR agonist was associated with a marked inhibition of caspase-9 activity and partial restoration of mitochondrial integrity. Our results provide the first evidence that C3aR and C5aR are both expressed in cerebellar granule cells during development and that C5a, but not C3a, is a potent inhibitor of apoptotic cell death in cultured granule neurons.

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C5a-induced expression of P-selectin in endothelial cells.

Cited by 440 publications

References 43 publications

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Lack of a Functional Alternative Complement Pathway Ameliorates Ischemic Acute Renal Failure in Mice

Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection

Characterization of C3a and C5a Receptors in Rat Cerebellar Granule Neurons during Maturation

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