Article

Dysregulated complement activation as a common pathway of injury in preeclampsia and other pregnancy complications.

Department of Obstetrics and Gynecology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
Placenta (Impact Factor: 3.29). 07/2010; 31(7):561-7. DOI: 10.1016/j.placenta.2010.03.010
Source: PubMed

ABSTRACT The complement system protects the host against invading organisms, initiates inflammation and dispose of immune complexes and the products of inflammatory injury. The complement system provides an important link between the innate and adaptive immune systems. Experimental observations suggest that increased complement activation causes and/or perpetuates inflammation during pregnancy. Recent studies suggest a link between complement activation and preeclampsia. Excessive activation or insufficient regulation of complement recruits leukocytes and unleashes potent inflammatory and anti-angiogenic mediators associated with placental insufficiency and maternal endothelial dysfunction characteristic of preeclampsia. We review the animal and human studies that link complement activation and pathogenic events in preeclampsia, present evidence that activation of the complement system is associated with the development of preeclampsia and provides new targets to prevent its complications.

Download full-text

Full-text

Available from: Jane E Salmon, Jul 05, 2015
0 Followers
 · 
108 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.
    Cell host & microbe 02/2013; 13(2):215-26. DOI:10.1016/j.chom.2013.01.010 · 12.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The intention of this review is to provide an overview of the potential role of neutrophil extracellular traps (NETs) in mammalian reproduction. Neutrophil NETs appear to be involved in various stages of the reproductive cycle, starting with fertility and possibly ending with fetal loss. The first suggestion that NETs may play a role in pregnancy-related disorders was in preeclampsia, where vast numbers were detected in the intervillous space of affected placentae. The induction of NETosis involved an auto-inflammatory component, mediated by the increased release of placental micro-debris in preeclampsia. This report was the first indicating that NETs may be associated with a human pathology not involving infection. Subsequently, NETs have since then been implicated in bovine or equine infertility, in that semen may become entrapped in the female reproductive tract during their passage to the oocyte. In this instance interesting species-specific differences are apparent, in that equine sperm evade entrapment via expression of a DNAse-like molecule, whereas highly motile bovine sperm, once free from seminal plasma (SP) that promotes interaction with neutrophils, appear impervious to NETs entrapment. Although still in the realm of speculation it is plausible that NETs may be involved in recurrent fetal loss mediated by anti-phospholipid antibodies, or perhaps even in fetal abortion triggered by infections with microorganisms such as L. monocytogenes or B. abortus.
    Frontiers in Immunology 11/2012; 3:362. DOI:10.3389/fimmu.2012.00362
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Complement activation plays a critical role in controlling inflammatory responses. To assess the role of complement during ovarian cancer progression, we crossed two strains of mice with genetic complement deficiencies with transgenic mice that develop epithelial ovarian cancer (TgMISIIR-TAg). TgMISIIR-TAg mice fully or partially deficient for complement factor 3 (C3) (Tg(+)C3(KO) and Tg(+)C3(HET), respectively) or fully deficient for complement factor C5a receptor (C5aR) (Tg(+)C5aR(KO)) develop either no ovarian tumors or tumors that were small and poorly vascularized compared to wild-type littermates (Tg(+)C3(WT), Tg(+)C5aR(WT)). The percentage of tumor infiltrating immune cells in Tg(+)C3(HET) tumors compared to Tg(+)C3(WT) controls was either similar (macrophages, B cells, myeloid-derived suppressor cells), elevated (effector T cells), or decreased (regulatory T cells). Regardless of these ratios, cytokine production by immune cells taken from Tg(+)C3(HET) tumors was reduced on stimulation compared to Tg(+)C3(WT) controls. Interestingly, CD31(+) endothelial cell (EC) function in angiogenesis was significantly impaired in both C3(KO) and C5aR(KO) mice. Further, using the C5aR antagonist PMX53, tube formation of ECs was shown to be C5a-dependent, possibly through interactions with the VEGF(165) but not VEGF(121) isoform. Finally, the mouse VEGF(164) transcript was underexpressed in C3(KO) livers compare to C3(WT) livers. Thus, we conclude that complement inhibition blocks tumor outgrowth by altering EC function and VEGF(165) expression.
    Neoplasia (New York, N.Y.) 11/2012; 14(11):994-1004. DOI:10.1593/neo.121262 · 5.40 Impact Factor