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Review
. 2009 Oct;13(10):4154-60.
doi: 10.1111/j.1582-4934.2009.00893.x. Epub 2009 Sep 1.

Sepsis, complement and the dysregulated inflammatory response

Peter A Ward  1 , Hongwei Gao
Affiliations
Review

Sepsis, complement and the dysregulated inflammatory response

Peter A Ward et al. J Cell Mol Med. 2009 Oct.

Abstract

Sepsis in human beings is a major problem involving many individuals and with a high death rate. Except for a single drug (recombinant activated protein C) that has been approved for treatment of septic patients, supportive measures represent the main clinical approach. There are many models of experimental sepsis, mostly in rodents. A commonly used model is cecal ligation and puncture (CLP). In this model, robust activation of complement occurs together with up-regulation of C5a receptors (C5aR, C5L2) in a variety of different organs (lungs, kidneys, liver, heart). In septic human beings there is abundant evidence for complement activation. Interception of C5a or its receptors in the CLP model greatly improves survival in septic rodents. There is compelling evidence that CLP causes an intense pro-inflammatory state and that C5a interaction with its receptors can be linked to apoptosis of the lymphoid system and cells of the adrenal medulla, loss of innate immune functions of blood neutrophils, consumptive coagulopathy and cardiac dysfunction. These findings may have implications for therapeutic interventions in human beings with sepsis.

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Figures

Fig 1
Fig 1
Effects of physiological levels of C5a (circa 10nM) on neutrophils, monocytes/macrophages and endothelial cells. The responses of the various cell types result in enhanced innate immune responses to infectious agents.
Fig 2
Fig 2
Signalling pathway activation by C5a on neutrophils, monocytes/macrophages and endothelial cells, resulting in compromised innate immunity, resistance of neutrophils to apoptosis, a cytokine storm and disseminated intravascular coagulation.
Fig 3
Fig 3
Perturbations in blood neutrophils during sepsis, resulting in the appearance of high levels of CCR-2, which now allows cells to respond to MCP-1 (CCR-2) and related ligands. This represents a ‘gain of function’ for neutrophils.
Fig 4
Fig 4
Interaction of C5a with C5aR during sepsis, resulting in compromised innate immune functions of neutrophils, together with activation markers and increased expression of pro-inflammatory mediators, coagulopathy, apoptosis of lymphoid cells, cardiomyopathy and apoptosis of adrenal medullary cells.
See this image and copyright information in PMC

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