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C5a Receptor Expression in Severe Sepsis and Septic Shock
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In patients with sepsis, the activation of the cascade systems, for example the complement system with the generation of C5a, is followed by a state of immunosuppression with impaired bactericidal capacity caused by suppression of the neutrophil granulocytes. To inhibit the C5a-induced systemic inflammatory and the following anti-inflammatory responses, different anti-C5a strategies have been successful in experimental models of sepsis. In animals and in healthy volunteers after injection of lipopolysaccharide (LPS), an up-regulation of the C5a receptor (C5aR) has been reported. Before designing clinical studies, it was of importance to increase the knowledge of C5a and C5aR regulation in humans.

At the time when the diagnosis of severe sepsis or septic shock can be established clinically, granulocyte C5aR expression, analysed by flow cytometer, was shown to be reduced, whereas monocyte C5aR expression was unchanged. There was a correlation between granulocyte C5aR expression and the severity of disease, as measured by the APACHE II score.

Ex vivo incubation of whole blood with LPS resulted in a reduction in granulocyte C5aR expression. Such a reduction was not found in isolated cells, indicating that the effect was mediated via plasma factors, such as C5a, IL-8 and TNF-α which all were shown to reduce C5aR expression ex vivo.

Although there was a trend between chemotaxis, as measured by migration in a modified Boyden chamber, and C5aR expression on granulocytes from patients with severe sepsis or septic shock or from healthy individuals, the correlation failed to reach statistical significance.

It is concluded that granulocyte C5aR expression is affected by several plasma factors and that a reduction is clinically evident at the time of the sepsis diagnosis. Reduced granulocyte C5aR expression is associated with an impaired chemotaxis but does not alone limit the chemotactic response.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 54
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 48
Keywords [en]
Communicable diseases, C5a receptor, granulocyte, severe sepsis, septic shock, chemotaxis, anti-C5a treatment, ex vivo incubation, C5a, interleukin-8, LPS
Keywords [sv]
Infektionssjukdomar
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:uu:diva-5832ISBN: 91-554-6275-8 (print)OAI: oai:DiVA.org:uu-5832DiVA, id: diva2:166564
Public defence
2005-06-02, Enghoffsalen, ing 50, bv, Akademiska sjukhuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-05-12 Created: 2005-05-12Bibliographically approved
List of papers
1. Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis
Open this publication in new window or tab >>Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis
Show others...
2002 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 6, no 4, p. 363-370Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Treatment of patients with severe sepsis with agents antagonising the effects of C5a has been proposed based on beneficial effects in animal experiments and in vitro studies demonstrating upregulation of the C5a receptor (CD88) on granulocytes by endotoxin.

MATERIALS AND METHODS: CD88 expression on leukocytes from 12 patients with severe sepsis or septic shock was analysed by flow cytometer, and serum complement factors C3a and C5b-9 were measured by enzyme immunoassay techniques.

RESULTS: The granulocyte CD88 expression on day 1 was lowered (36; range, 2-59) in comparison with controls (63; range, 25-88) (P < 0.001), despite complement activation, while the monocyte CD88 expression was unchanged. The receptor reduction correlated significantly to the APACHE II score (r2 = 0.35, P < 0.05). The recovery of CD88 expression was slow.

DISCUSSION: In contrast to the findings in animals, it is concluded that granulocyte CD88 expression is reduced at the time when the diagnosis of severe sepsis or septic shock can clinically be made. The reason for this needs further investigation but it may be due to a previous complement activation or to cytokine effects.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93166 (URN)12225614 (PubMedID)
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2017-12-14Bibliographically approved
2. Differential expression of the C5a receptor and complement receptors 1 and 3 after LPS stimulation of neutrophils and monocytes
Open this publication in new window or tab >>Differential expression of the C5a receptor and complement receptors 1 and 3 after LPS stimulation of neutrophils and monocytes
2004 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 60, no 5, p. 494-499Article in journal (Refereed) Published
Abstract [en]

Animal experiments recently suggested that administration of anti-C5a, anti-C5a receptor or soluble complement receptor type-1 may be of value in the treatment of septic shock. Because results regarding C5a receptor expression (C5a-R, CD-88) have been found to differ between septic animals and patients, the aim of this study was to investigate the neutrophil and monocyte receptor expression of CD-88 and complement receptor-1 (CR-1, CD-35) after stimulation with lipopolysaccharide (LPS) ex vivo. Whole blood or isolated neutrophils and monocytes from healthy people were incubated with LPS in a dose range of 0.1-1000 ng/ml. The expressions of CD-88 and CD-35 were analysed by means of flow cytometry. For comparison, the expressions of complement receptor-3 (CR-3, CD-11b/CD-18), Fc-gamma receptor type-I (CD-64) and CEACAM-8 (CD-66b) were also investigated. In whole blood, CD-88 expression on neutrophils was reduced (P < 0.05). The expressions of CD-35 and CD-11b were increased both on neutrophils (P < 0.001; P < 0.05) and on monocytes (P < 0.001; P < 0.001). No effect was observed on isolated cells. In agreement with the findings in septic patients, LPS reduced the neutrophil C5a-R expression, whereas the expressions of CR-1 and CR-3 were increased. The effects of LPS were indirect and were mediated via factors in the blood. The clinical significance of this is not known, but may be associated with decreased chemotaxis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93167 (URN)10.1111/j.0300-9475.2004.01499.x (DOI)15541042 (PubMedID)
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2017-12-14Bibliographically approved
3. C5a, interleukin-8 and tumour necrosis factor-alpha-induced changes in granulocyte and monocyte expression of complement receptors in whole blood and on isolated leukocytes
Open this publication in new window or tab >>C5a, interleukin-8 and tumour necrosis factor-alpha-induced changes in granulocyte and monocyte expression of complement receptors in whole blood and on isolated leukocytes
2006 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 63, no 3, p. 208-216Article in journal (Refereed) Published
Abstract [en]

Treatments targeting complement receptors have been demonstrated to improve outcome in experimental sepsis. The regulation of the complement receptors in sepsis is not clear. Lipopolysaccharide (LPS) stimulation of granulocytes ex vivo has been shown to reduce C5a receptor (CD88) expression and to increase CD35 and CD11b/CD18 expressions in whole blood but not on isolated cells, indicating an indirect effect mediated via factors in the blood. With the aim to study whether these effects could be attributed to C5a, tumour necrosis factor (TNF)-alpha and interleukin (IL)-8, whole blood or isolated granulocytes and monocytes from healthy individuals were investigated. After incubation with C5a in a dose range of 1 x 10(-9)-1 x 10(-7) mol/l, and TNF-alpha and IL-8 at doses of 1-100 ng/ml, the expressions of the complement receptors CD88, CD35, CD11b/CD18 were analysed by flow cytometry. Incubation with C5a reduced granulocyte CD88 expression by 44+/-6.9% and 82+/-4.2%, whereas monocyte CD88 expression decreased by 21+/-4.0 and 30+/-17% (whole blood and isolated cells). IL-8 and TNF-alpha incubation of granulocytes induced similar results. Granulocyte CD35 expression was significantly increased by 367, 175 and 336% by C5a, TNF-alpha, IL-8, respectively; CD11b expression was similarly increased. Consistent with findings in septic patients and after LPS incubation, it is concluded that all stimuli reduced granulocyte CD88 expression, whereas CD35 and CD11b were increased.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93168 (URN)10.1111/j.1365-3083.2006.01724.x (DOI)16499574 (PubMedID)
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2017-12-14Bibliographically approved
4. C5a receptor expression and impaired chemotaxis in granulocytes from septic patients and from healthy subjects after exposure to C5a and interleukin-8 ex vivo
Open this publication in new window or tab >>C5a receptor expression and impaired chemotaxis in granulocytes from septic patients and from healthy subjects after exposure to C5a and interleukin-8 ex vivo
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-93169 (URN)
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2010-01-13Bibliographically approved

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