Both Plasma- and Leukocyte-Associated C5a Are Essential for Assessment of C5a Generation In Vivo

Hetland, Geir; Moen, Oddvar; Bergh, Kåre; Høgåsen, K; Hack, C. E.; Te, Mollnes; Fosse, Erik

doi:10.1016/s0003-4975(96)01255-6

Cited by 16 publications

(14 citation statements)

References 19 publications

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“…12 The stronger binding of C5a to the complement receptors could explain the delayed course of C5a activation compared with C3a activation. 15 In contrast to the results of Vallhonrat et al in two adults, the sC5b-9 values of the investigated six neonates did not decline to the beginning values after 2 days. Only C3a concentrations decreased after the initial peak at 1 h to values similar to the initial value at 24 h, confirming the results of Hocker et al 4 and Plötz et al 7 Concentrations of C5a and sC5b-9 showed a second increase at 64 h due to secondary infection of two newborns during ECMO, with extremely high values for sC5b-9 and C5a.…”

Section: Discussioncontrasting

confidence: 88%

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Graulich

Sonntag

Marcinkowski

et al. 2002

Mediators of Inflammation

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Complment activation during extracorporeal membrane oxygenation (ECMO) in newborns can be caused by both the underlying disease processes and by blood contact with the ECMO circuit. We investigated the relative importance of these mechanisms by measuring C3a, C5a and sC5b-9 before, during and after neonatal ECMO in six consecutive newborn patients using enzyme-linked immunoassay. In addition complement activation during in vitro ECMO with repeated flow of the same blood volume was measured using blood from healthy adult donors. C3a increased significantly in vivo after 1 h (from 1035+/-193 to 1865+/-419 microg/l) and in vitro ECMO (from 314+/-75 to 1962+/-1062 microg/l). C5a increased during ECMO without significant differences between in vivo and in vitro activation. In neonatal patients, sC5b-9 rose faster than in vitro, but the rapid increase was also significant for in vitro experiments (in vivo: from 328+/-63 to 1623+/-387 microg/l after 2 h; and in vitro: from 78+/-32 to 453+/-179 microg/l after 8 h). After this initial peak at 1-2 h, complement activation decreased gradually until 2-3 days after the initiation of ECMO. We conclude that in newborns the rapid activation of the complement system after the start of ECMO is predominantly caused by contact with artificial surfaces rather than the patient's underlying disease.

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Section: Discussioncontrasting

confidence: 88%

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Graulich

Sonntag

Marcinkowski

et al. 2002

Mediators of Inflammation

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“…However, it is not clear whether CPN completely desarginates h C5a before binding to C5aR, which is unlikely given the importance of Arg 74 on h C5a for C5aR binding and signaling. In fact, some studies have also evidenced that internalization of C5aR involves the h C5a with intact antigenicity (Hetland et al, 1997). One possible explanation could be that the docking of the h C5a to C5aR confers conformational rigidity to Arg 74 , which helps the membrane-bound carboxypeptidase M (CPM) (Marquez-Curtis et al, 2008) in converting the h C5a to des-Arg 74 -h C5a, thereby preparing C5aR for signal attenuation and subsequent internalization.…”

Section: Discussionmentioning

confidence: 99%

Allosterism in human complement component 5a (^hC5a): a damper of C5a receptor (C5aR) signaling

Rana

Sahoo

Majhi

2015

Journal of Biomolecular Structure and Dynamics

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The phenomena of allosterism continues to advance the field of drug discovery, by illuminating gainful insights for many key processes, related to the structure-function relationships in proteins and enzymes, including the transmembrane G-protein coupled receptors (GPCRs), both in normal as well as in the disease states. However, allosterism is completely unexplored in the native protein ligands, especially when a small covalent change significantly modulates the pharmacology of the protein ligands toward the signaling axes of the GPCRs. One such example is the human C5a ((h)C5a), the potent cationic anaphylatoxin that engages C5aR and C5L2 to elicit numerous immunological and non-immunological responses in humans. From the recently available structure-function data, it is clear that unlike the mouse C5a ((m)C5a), the (h)C5a displays conformational heterogeneity. However, the molecular basis of such conformational heterogeneity, otherwise allosterism in (h)C5a and its precise contribution toward the overall C5aR signaling is not known. This study attempts to decipher the functional role of allosterism in (h)C5a, by exploring the inherent conformational dynamics in (m)C5a, (h)C5a and in its point mutants, including the proteolytic mutant des-Arg(74)-(h)C5a. Prima facie, the comparative molecular dynamics study, over total 500 ns, identifies Arg(74)-Tyr(23) and Arg(37)-Phe(51) "cation-π" pairs as the molecular "allosteric switches" on (h)C5a that potentially functions as a damper of C5aR signaling.

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“…As shown by the similar rise in plasma samples, no cellular interaction or contact with destroyed cells is necessary to initiate the complement and contact cascade in acidosis. The differences between heparin blood and plasma may be due to two factors: (1) binding of C5a and factor XIIa to receptors of blood cells, 12 which results in lower C5a and factor XIIa values in blood compared with plasma by low amount of added lactic acid; and (2) additional activation by contact with destroyed cell membranes and receptor changes in blood, which results in higher C5a and factor XIIa values in blood samples by lower pH values causing cell destruction. This haemolytic effect is documented by raising potassium concentration in the samples.…”

Section: Discussionmentioning

confidence: 99%

in vitro activation of complement and contact system by lactic acidosis

Sonntag

Emeis

Strauss

et al. 1998

Mediators of Inflammation

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The activation of complement and contact systems occurs in reperfusion injuries with initial tissue hypoxia, and lactic acidosis such as mycardial infarction and birth asphyxia. The aim of our experiment was the formal proof of activation by sole lactic acidosis. Lactic acid was added to blood and plasma samples from 10 healthy volunteers. C5a and factor XIIa were measured by EIA after incubation at 37 degrees C for 1 h. Both concentrations increased (P < 0.0001 by Friedman analysis) in blood and plasma samples with increasing amount of added lactic acid. Lactic acidosis can activate C5 from the complement system and factor XII from the contact system directly, even in the absence of cellular components.

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Both Plasma- and Leukocyte-Associated C5a Are Essential for Assessment of C5a Generation In Vivo

Abstract: Both plasma-and leukocyte-associated C5a are essential for assessment of C5a generation in vivo Hetland, G.; Moen, O.; Bergh, K.; Hogasen, K.; Hack, C.E.; Mollnes, T.E.; Fosse, E.

Cited by 16 publications

References 19 publications

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Allosterism in human complement component 5a (^hC5a): a damper of C5a receptor (C5aR) signaling

in vitro activation of complement and contact system by lactic acidosis

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Both Plasma- and Leukocyte-Associated C5a Are Essential for Assessment of C5a Generation In Vivo

Abstract: Both plasma-and leukocyte-associated C5a are essential for assessment of C5a generation in vivo Hetland, G.; Moen, O.; Bergh, K.; Hogasen, K.; Hack, C.E.; Mollnes, T.E.; Fosse, E.

Cited by 16 publications

References 19 publications

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Complement activation by in vivo neonatal and in vitro extracorporeal membrane oxygenation

Allosterism in human complement component 5a (hC5a): a damper of C5a receptor (C5aR) signaling

in vitro activation of complement and contact system by lactic acidosis

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Allosterism in human complement component 5a (^hC5a): a damper of C5a receptor (C5aR) signaling