Bench-to-bedside review: The role of C1-esterase inhibitor in sepsis and other critical illnesses

Singer, Mervyn; Jones, Annie

doi:10.1186/cc9304

Cited by 33 publications

(21 citation statements)

References 62 publications

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“…This occurs via detection of PAMPs followed by recruitment and activation of proteases. Complement pathway activation results in opsonisation of bacteria with C3b to facilitate phagocytosis, generation of membrane attack complex for bacterial cell lysis, and generation of pro-inflammatory chemokine anaphylotoxins such as C3a and C5a, which are central mediators of the inflammatory hub in sepsis [7,50,97-99]. …”

Section: The Biological Rationale For Administering Ivig In Sepsismentioning

confidence: 99%

Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

et al. 2011

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Sepsis represents a dysregulated host response to infection, the extent of which determines the severity of organ dysfunction and subsequent outcome. All trialled immunomodulatory strategies to date have resulted in either outright failure or inconsistent degrees of success. Intravenous immunoglobulin (IVIg) therapy falls into the latter category with opinion still divided as to its utility. This article provides a narrative review of the biological rationale for using IVIg in sepsis. A literature search was conducted using the PubMed database (1966 to February 2011). The strategy included the following text terms and combinations of these: IVIg, intravenous immune globulin, intravenous immunoglobulin, immunoglobulin, immunoglobulin therapy, pentaglobin, sepsis, inflammation, immune modulation, apoptosis. Preclinical and extrapolated clinical data of IVIg therapy in sepsis suggests improved bacterial clearance, inhibitory effects upon upstream mediators of the host response (for example, the nuclear factor kappa B (NF-κB) transcription factor), scavenging of downstream inflammatory mediators (for example, cytokines), direct anti-inflammatory effects mediated via Fcγ receptors, and a potential ability to attenuate lymphocyte apoptosis and thus sepsis-related immunosuppression. Characterizing the trajectory of change in immunoglobulin levels during sepsis, understanding mechanisms contributing to these changes, and undertaking IVIg dose-finding studies should be performed prior to further large-scale interventional trials to enhance the likelihood of a successful outcome.

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Section: The Biological Rationale For Administering Ivig In Sepsismentioning

confidence: 99%

Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

et al. 2011

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“…Poppelaars et al showed that treatment of BD rats with rhC1INH resulted in reduced renal mRNA expression and serum levels of IL‐6, improved renal function, and reduced renal injury prior to transplantation. These observations are supported further by multiple studies demonstrating the protective anti‐inflammatory effect of C1 blockade in models of sepsis, as well as renal, neurological, myocardial, and intestinal IRI . Although rodent models of renal IRI indicate a predominant role for the alternative pathway in complement‐mediated renal injury, recent reports suggest that CP and LP are critical in the pathogenesis of IRI, DGF, and acute rejection in large animal models and humans …”

Section: Discussionmentioning

confidence: 69%

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

Danobeitia¹,

Zens²,

Chlebeck³

et al. 2020

American Journal of Transplantation

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Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival.BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 -vehicle, G2 -rhC1INH+heparin, and G3 -heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase-associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation. 1514 | DANOBEITIA ET Al. K E Y W O R D S animal models: nonhuman primate, complement biology, delayed graft function (DGF), donors and donation: donation after brain death (DBD), immunosuppression/immune modulation, ischemia reperfusion injury (IRI), kidney transplantation/nephrology, translational research/ science 1 | INTRODUC TI ON Delayed graft function (DGF) manifests as a consequence of ischemia-reperfusion injury (IRI) and is characterized by acute kidney injury (AKI) within 7 days of transplant, requiring life-sustaining dialysis. 1 The incidence of DGF in kidney transplants from brain dead (BD) donors is approximately 26% in the United States, and this rate can reach as high as 37% in kidneys from older donors and those subjected to extended cold ischemia >36 hours. 2-4 In addition to complications related to AKI in the peritransplant period, development of DGF is an important risk factor for acute cellular rejection, antibody-mediated rejection (AMR), and reduced

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“…Moreover, C1-INH exhibited therapeutic effects in other diseases and clinical situations [25,24] and may have therapeutic potential in numerous diseases, where the tightly cross-linked complement and contact system are concurrently activated [2]. Due to their C1-INH potentiating effect, sulfated glycans may offer an option to improve either the efficacy of therapeutically applied C1-INH or the activity of endogenous C1-INH.…”

Section: Discussionmentioning

confidence: 99%

“…These may also be obstacles to the application of C1-INH in further indications, although clinical studies showed beneficial effects of C1-INH also in other disease states like sepsis, gram-negative endotoxic shock, vascular leak syndrome, transplant rejection, ischemia-reperfusion injury, myocardial infarction, and emergency coronary artery bypass surgery [24,25]. …”

Section: Introductionmentioning

confidence: 99%

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

2016

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The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system.

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Bench-to-bedside review: The role of C1-esterase inhibitor in sepsis and other critical illnesses

Abstract: The purpose of this bench-to-bedside review is to summarize the literature relating to complement activation in sepsis and other critical illnesses and the role of C1-esterase inhibitor (C1 INH) as a potential therapy.

Cited by 33 publications

References 62 publications

Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

Bench-to-bedside review: Immunoglobulin therapy for sepsis - biological plausibility from a critical care perspective

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

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