Complement activation during storage of blood under normal blood bank conditions. Effects of proteinase inhibitors and leukocyte depletion

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 3071-3075
Author(s):  
M Schleuning ◽  
M Schmid-Haslbeck ◽  
H Utz ◽  
M Jochum ◽  
M Heim ◽  
...  
Keyword(s):  
Complement Activation ◽  
Whole Blood ◽  
Proteinase Inhibitors ◽  
Elastase Inhibitor ◽  
Leukocyte Depletion ◽  
Eglin C ◽  
Lysosomal Proteinase ◽  
Polyvalent Proteinase Inhibitor ◽  
Plastic Surfaces ◽  
The Complement System

During storage of CPD-A1 preserved whole blood factors of the complement cascade become activated, as evidenced by a rapid increase in the concentrations of C3a-desArg and C4a-desArg. After 10 to 14 days of whole blood storage, the elevations of C3a and C4a levels were highly significant. This increase was paralleled by an increase in the concentration of the lysosomal proteinase elastase from polymorphonuclear (PMN) granulocytes. By contrast, the concentration of the C3 activator complex C4b2b remained unchanged even after 3 weeks of storage. The supplementation of the anticoagulant CPD-A1 with the polyvalent-proteinase-inhibitor aprotinin and the specific elastase- inhibitor eglin C failed to inhibit complement activation, whereas leukocyte depletion could partially abolish the increase of the concentration of C4a, but had no effect on C3a concentrations. These observations support the notion that cleavage of C4 during storage of whole blood is partially leukocyte dependent, whereas the activation of C3 is possibly caused by the activation of the alternate pathway of the complement system by contact of plasma with plastic surfaces.

scholarly journals Complement activation during storage of blood under normal blood bank conditions. Effects of proteinase inhibitors and leukocyte depletion

Blood ◽  
1992 ◽  
Vol 79 (11) ◽  
pp. 3071-3075 ◽  
Author(s):  
M Schleuning ◽  
M Schmid-Haslbeck ◽  
H Utz ◽  
M Jochum ◽  
M Heim ◽  
...  
Keyword(s):  
Complement Activation ◽  
Whole Blood ◽  
Proteinase Inhibitors ◽  
Elastase Inhibitor ◽  
Leukocyte Depletion ◽  
Eglin C ◽  
Lysosomal Proteinase ◽  
Polyvalent Proteinase Inhibitor ◽  
Plastic Surfaces ◽  
The Complement System

Abstract During storage of CPD-A1 preserved whole blood factors of the complement cascade become activated, as evidenced by a rapid increase in the concentrations of C3a-desArg and C4a-desArg. After 10 to 14 days of whole blood storage, the elevations of C3a and C4a levels were highly significant. This increase was paralleled by an increase in the concentration of the lysosomal proteinase elastase from polymorphonuclear (PMN) granulocytes. By contrast, the concentration of the C3 activator complex C4b2b remained unchanged even after 3 weeks of storage. The supplementation of the anticoagulant CPD-A1 with the polyvalent-proteinase-inhibitor aprotinin and the specific elastase- inhibitor eglin C failed to inhibit complement activation, whereas leukocyte depletion could partially abolish the increase of the concentration of C4a, but had no effect on C3a concentrations. These observations support the notion that cleavage of C4 during storage of whole blood is partially leukocyte dependent, whereas the activation of C3 is possibly caused by the activation of the alternate pathway of the complement system by contact of plasma with plastic surfaces.

Aberrant activation of complement system in renal grafts is mediated by cold storage

2021 ◽  
Author(s):  
Sorena Lo ◽  
Li Jiang ◽  
Savannah Stacks ◽  
Haixia Lin ◽  
Nirmala Parajuli
Keyword(s):  
Cold Storage ◽  
Complement System ◽  
Complement Activation ◽  
Renal Tubules ◽  
Renal Transplants ◽  
Reducing Conditions ◽  
Tnf Α ◽  
Renal Grafts ◽  
The Impact ◽  
The Complement System

Aberrant complement activation leads to tissue damage during kidney transplantation, and it is recognized as an important target for therapeutic intervention (6, 19, 35, 64). However, it is not clear whether cold storage (CS) triggers the complement pathway in transplanted kidneys. The goal of this study was to determine the impact of CS on complement activation in renal transplants. Male Lewis and Fischer rats were used, and donor rat kidneys were exposed to 4 h or 18 h of CS followed by transplantation (CS+Transplant). To study CS-induced effects, a group with no CS was included in which the kidney was removed and transplanted back to the same rat (autotransplantation, ATx). Complement proteins (C3 and C5b-9) were evaluated with western blotting (reducing and non-reducing conditions) and immunostaining. Western blot of renal extracts or serum indicated that the levels of C3 and C5b-9 increased after CS+Transplant compared to ATx. Quite strikingly, intracellular C3 was profoundly elevated within renal tubules after CS+Transplant but was absent in Sham or ATx groups, which showed only extratubular C3. Similarly, C5b-9 immunofluorescence staining of renal sections showed an increase in C5b-9 deposits in kidneys after CS+Transplant. Real-time PCR (SYBR Green) showed increased expression of CD11b and CD11c, components of complement receptors 3 and 4, respectively, as well as inflammatory markers such as TNF-α. In addition, recombinant TNF-α significantly increased C3 levels in renal cells. Collectively, these results demonstrate that CS activates the complement system in renal transplants.

scholarly journals A morphological transformation in respiratory syncytial virus leads to enhanced complement deposition

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jessica P Kuppan ◽  
Margaret D Mitrovich ◽  
Michael D Vahey
Keyword(s):  
Respiratory Syncytial Virus ◽  
Complement Activation ◽  
Protective Role ◽  
Respiratory Pathogen ◽  
Classical Pathway ◽  
Morphological Transformation ◽  
Virus Particles ◽  
Syncytial Virus ◽  
The Complement System ◽  
Complement Deposition

The complement system is a critical host defense against infection, playing a protective role that can also enhance disease if dysregulated. Although many consequences of complement activation during viral infection are well established, mechanisms that determine the extent to which viruses activate complement remain elusive. Here, we investigate complement activation by human respiratory syncytial virus (RSV), a filamentous respiratory pathogen that causes significant morbidity and mortality. By engineering a strain of RSV harboring tags on the surface glycoproteins F and G, we are able to monitor opsonization of single RSV particles using fluorescence microscopy. These experiments reveal an antigenic hierarchy, where antibodies that bind toward the apex of F in either the pre- or postfusion conformation activate the classical pathway whereas other antibodies do not. Additionally, we identify an important role for virus morphology in complement activation: as viral filaments age, they undergo a morphological transformation which lowers the threshold for complement deposition through changes in surface curvature. Collectively, these results identify antigenic and biophysical characteristics of virus particles that contribute to the formation of viral immune complexes, and suggest models for how these factors may shape disease severity and adaptive immune responses to RSV.

scholarly journals Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

2017 ◽  
Vol 114 (15) ◽  
pp. 3987-3992 ◽  
Author(s):  
Tamara L. Lenis ◽  
Shanta Sarfare ◽  
Zhichun Jiang ◽  
Marcia B. Lloyd ◽  
Dean Bok ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinal Pigment Epithelium ◽  
Complement System ◽  
Complement Activation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Host Cells ◽  
Etiologic Factor ◽  
Photoreceptor Degeneration ◽  
The Complement System

Recessive Stargardt macular degeneration (STGD1) is caused by mutations in the gene for the ABCA4 transporter in photoreceptor outer segments. STGD1 patients and Abca4−/− (STGD1) mice exhibit buildup of bisretinoid-containing lipofuscin pigments in the retinal pigment epithelium (RPE), increased oxidative stress, augmented complement activation and slow degeneration of photoreceptors. A reduction in complement negative regulatory proteins (CRPs), possibly owing to bisretinoid accumulation, may be responsible for the increased complement activation seen on the RPE of STGD1 mice. CRPs prevent attack on host cells by the complement system, and complement receptor 1-like protein y (CRRY) is an important CRP in mice. Here we attempted to rescue the phenotype in STGD1 mice by increasing expression of CRRY in the RPE using a gene therapy approach. We injected recombinant adeno-associated virus containing the CRRY coding sequence (AAV-CRRY) into the subretinal space of 4-wk-old Abca4−/− mice. This resulted in sustained, several-fold increased expression of CRRY in the RPE, which significantly reduced the complement factors C3/C3b in the RPE. Unexpectedly, AAV-CRRY–treated STGD1 mice also showed reduced accumulation of bisretinoids compared with sham-injected STGD1 control mice. Furthermore, we observed slower photoreceptor degeneration and increased visual chromophore in 1-y-old AAV-CRRY–treated STGD1 mice. Rescue of the STGD1 phenotype by AAV-CRRY gene therapy suggests that complement attack on the RPE is an important etiologic factor in STGD1. Modulation of the complement system by locally increasing CRP expression using targeted gene therapy represents a potential treatment strategy for STGD1 and other retinopathies associated with complement dysregulation.

Possibility to Improve Preservation of Whole Blood by Leukocyte-Depletion before Storage

Vox Sanguinis ◽  
1990 ◽  
Vol 59 (2) ◽  
pp. 78-82 ◽  
Author(s):  
C. Riedner ◽  
M. U. Heim ◽  
W. Mempel ◽  
W. Wilmanns
Keyword(s):  
Whole Blood ◽  
Leukocyte Depletion

scholarly journals Complement Activation and Complement-Dependent Inflammation by Neisseria meningitidis Are Independent of Lipopolysaccharide

2004 ◽  
Vol 72 (6) ◽  
pp. 3344-3349 ◽  
Author(s):  
Tom Sprong ◽  
Anne-Sophie W. Møller ◽  
Anna Bjerre ◽  
Elisabeth Wedege ◽  
Peter Kierulf ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Complement Activation ◽  
Oxidative Burst ◽  
Whole Blood ◽  
Meningococcal Sepsis ◽  
Necrosis Factor Alpha ◽  
Chemokine Production ◽  
Inflammatory Protein ◽  
Activation Products ◽  
Factor Alpha

ABSTRACT Fulminant meningococcal sepsis has been termed the prototypical lipopolysaccharide (LPS)-mediated gram-negative septic shock. Systemic inflammation by activated complement and cytokines is important in the pathogenesis of this disease. We investigated the involvement of meningococcal LPS in complement activation, complement-dependent inflammatory effects, and cytokine or chemokine production. Whole blood anticoagulated with lepirudin was stimulated with wild-type Neisseria meningitidis H44/76 (LPS+), LPS-deficient N. meningitidis H44/76lpxA (LPS−), or purified meningococcal LPS (NmLPS) at concentrations that were relevant to meningococcal sepsis. Complement activation products, chemokines, and cytokines were measured by enzyme-linked immunosorbent assays, and granulocyte CR3 (CD11b/CD18) upregulation and oxidative burst were measured by flow cytometry. The LPS+ and LPS− N. meningitidis strains both activated complement effectively and to comparable extents. Purified NmLPS, used at a concentration matched to the amount present in whole bacteria, did not induce any complement activation. Both CR3 upregulation and oxidative burst were also induced, independent of LPS. Interleukin-1β (IL-1β), tumor necrosis factor alpha, and macrophage inflammatory protein 1α production was predominantly dependent on LPS, in contrast to IL-8 production, which was also markedly induced by the LPS− meningococci. In this whole blood model of meningococcal sepsis, complement activation and the immediate complement-dependent inflammatory effects of CR3 upregulation and oxidative burst occurred independent of LPS.

Compstatin Inhibits Complement and Cellular Activation in Whole Blood in Two Models of Extracorporeal Circulation

Blood ◽  
1998 ◽  
Vol 92 (5) ◽  
pp. 1661-1667 ◽  
Author(s):  
Bo Nilsson ◽  
Rolf Larsson ◽  
Jaan Hong ◽  
Graciela Elgue ◽  
Kristina Nilsson Ekdahl ◽  
...  
Keyword(s):  
Extracorporeal Circulation ◽  
Complement Activation ◽  
Whole Blood ◽  
Polymer Surface ◽  
Inhibitory Effect ◽  
Cell Counts ◽  
Complement Component C3 ◽  
Precursor Peptide ◽  
Extracorporeal Circuits ◽  
American Society

Abstract Recently, a C3-binding cyclic synthetic peptide (Compstatin) has been identified that binds to complement component C3 and inhibits complement activation. Here we have examined the influence of Compstatin on complement activation and its indirect effects on cellular responses in whole blood in two models for extracorporeal circulation. Compstatin effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/ C3 fragments to the polymer surface. As a result of the inhibition of complement activation, the activation of polymorphonuclear leukocytes (PMNs; as assessed by the expression of CD11b) and the binding of these cells (CD16+) to the polymer surface were almost completely lost. In contrast, blood cell counts were not affected. Using surface plasmon resonance technology, we have confirmed that Compstatin exerts its inhibitory effect on complement activation by binding to native C3. These data show that complement activation, leading to activation and binding of PMNs to the biomaterial surface, can be abolished by the addition of Compstatin. The properties of Compstatin make Compstatin a promising drug for use in extracorporeal circuits to avoid bioincompatibility reactions, eg, during cardiopulmonary bypass, but also a favorable precursor peptide for the development of an anticomplement drug for oral use. © 1998 by The American Society of Hematology.

scholarly journals Pretreatment with atorvastatin ameliorates cobra venom factor-induced acute lung inflammation in mice

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jing Guo ◽  
Min Li ◽  
Yi Yang ◽  
Lin Zhang ◽  
Li-wei Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Protein Content ◽  
Complement System ◽  
Complement Activation ◽  
Lung Inflammation ◽  
Acute Lung Inflammation ◽  
Tnf Α ◽  
The Complement System

Abstract Background The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study. Methods ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting. Results The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung. Conclusion These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.

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