Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis

AbstractComplement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis.This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.

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Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

Current Alzheimer Research ◽

10.2174/1567205014666171128102557 ◽

2018 ◽

Vol 15 (6) ◽

pp. 531-543 ◽

Cited By ~ 4

Author(s):

Dominik Szwajgier ◽

Ewa Baranowska-Wojcik ◽

Kamila Borowiec

Keyword(s):

Phenolic Acids ◽

Ex Vivo ◽

Amyloid Β ◽

Inhibitory Effect ◽

In Vivo Studies ◽

Amyloid Β Peptide ◽

Beneficial Effects ◽

Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

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Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00173.2013 ◽

2013 ◽

Vol 305 (11) ◽

pp. L844-L855 ◽

Cited By ~ 47

Author(s):

Ming-Yuan Jian ◽

Mikhail F. Alexeyev ◽

Paul E. Wolkowicz ◽

Jaroslaw W. Zmijewski ◽

Judy R. Creighton

Keyword(s):

Endothelial Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Ex Vivo ◽

Endothelial Permeability ◽

Beneficial Effects ◽

Isolated Lung

Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(α-d-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient ( Kf) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-α1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-α1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-α1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.

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Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

American Journal of Nephrology ◽

10.1159/000451060 ◽

2016 ◽

Vol 45 (1) ◽

pp. 49-59 ◽

Cited By ~ 29

Author(s):

Julia Cordelia Hempel ◽

Felix Poppelaars ◽

Mariana Gaya da Costa ◽

Casper F.M. Franssen ◽

Thomas P.G. de Vlaam ◽

...

Keyword(s):

Healthy Volunteers ◽

Complement Activation ◽

Ex Vivo ◽

Ferric Carboxymaltose ◽

Hypersensitivity Reactions ◽

Iron Dextran ◽

Iv Iron ◽

Ex Vivo Assay

Background: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA). Methods: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients. Results: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation. Conclusion: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

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A targeted complement-dependent strategy to improve the outcome of mAb therapy, and characterization in a murine model of metastatic cancer

Blood ◽

10.1182/blood-2011-10-383232 ◽

2012 ◽

Vol 119 (25) ◽

pp. 6043-6051 ◽

Cited By ~ 17

Author(s):

Michelle Elvington ◽

Yuxiang Huang ◽

B. Paul Morgan ◽

Fei Qiao ◽

Nico van Rooijen ◽

...

Keyword(s):

Immune Response ◽

Tumor Cell ◽

Complement Activation ◽

Metastatic Cancer ◽

Protein Targets ◽

Complement Inhibitors ◽

Activation Products ◽

Cellular Immune

Abstract Complement inhibitors expressed on tumor cells provide an evasion mechanism against mAb therapy and may modulate the development of an acquired antitumor immune response. Here we investigate a strategy to amplify mAb-targeted complement activation on a tumor cell, independent of a requirement to target and block complement inhibitor expression or function, which is difficult to achieve in vivo. We constructed a murine fusion protein, CR2Fc, and demonstrated that the protein targets to C3 activation products deposited on a tumor cell by a specific mAb, and amplifies mAb-dependent complement activation and tumor cell lysis in vitro. In syngeneic models of metastatic lymphoma (EL4) and melanoma (B16), CR2Fc significantly enhanced the outcome of mAb therapy. Subsequent studies using the EL4 model with various genetically modified mice and macrophage-depleted mice revealed that CR2Fc enhanced the therapeutic effect of mAb therapy via both macrophage-dependent FcγR-mediated antibody-dependent cellular cytotoxicity, and by direct complement-mediated lysis. Complement activation products can also modulate adaptive immunity, but we found no evidence that either mAb or CR2Fc treatment had any effect on an antitumor humoral or cellular immune response. CR2Fc represents a potential adjuvant treatment to increase the effectiveness of mAb therapy of cancer.

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Biomechanical-Based Protocol for in vitro Study of Cartilage Response to Cyclic Loading: A Proof-of-Concept in Knee Osteoarthritis

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.634327 ◽

2021 ◽

Vol 9 ◽

Author(s):

Paolo Caravaggi ◽

Elisa Assirelli ◽

Andrea Ensini ◽

Maurizio Ortolani ◽

Erminia Mariani ◽

...

Keyword(s):

Ex Vivo ◽

In Vitro Study ◽

Cartilage Explants ◽

Joint Loading ◽

Design And Optimization ◽

Cartilage Metabolism ◽

Beneficial Effects ◽

Physiological Loading

Osteoarthritis (OA) is an evolving disease and a major cause of pain and impaired mobility. A deeper understanding of cartilage metabolism in response to loading is critical to achieve greater insight into OA mechanisms. While physiological joint loading helps maintain cartilage integrity, reduced or excessive loading have catabolic effects. The main scope of this study is to present an original methodology potentially capable to elucidate the effect of cyclic joint loading on cartilage metabolism, to identify mechanisms involved in preventing or slowing down OA progression, and to provide preliminary data on its application. In the proposed protocol, the combination of biomechanical data and medical imaging are integrated with molecular information about chondrocyte mechanotransduction and tissue homeostasis. The protocol appears to be flexible and suitable to analyze human OA knee cartilage explants, with different degrees of degeneration, undergoing ex vivo realistic cyclic joint loading estimated via gait analysis in patients simulating mild activities of daily living. The modulation of molecules involved in cartilage homeostasis, mechanotransduction, inflammation, pain and wound healing can be analyzed in chondrocytes and culture supernatants. A thorough analysis performed with the proposed methodology, combining in vivo functional biomechanical evaluations with ex vivo molecular assessments is expected to provide new insights on the beneficial effects of physiological loading and contribute to the design and optimization of non-pharmacological treatments limiting OA progression.

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Complement and the prothrombotic state

Blood ◽

10.1182/blood.2020007206 ◽

2021 ◽

Author(s):

Christoph Q Schmidt ◽

Hubert Schrezenmeier ◽

David Kavanagh

Keyword(s):

Complement Activation ◽

Ex Vivo ◽

Atypical Hemolytic Uremic Syndrome ◽

Protein Losing Enteropathy ◽

Mortality And Morbidity ◽

Life Threatening ◽

Uremic Syndrome ◽

Clinical Conditions ◽

Distinct Features

In 2007 and 2009 the regulatory approval of the first-in-class complement inhibitor Eculizumab has revolutionized the clinical management of two rare, life-threatening clinical conditions: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). While being completely distinct diseases affecting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology and clinical presentation. An imbalance between complement activation and regulation at host surfaces underlies both diseases precipitating in severe thrombotic events that are largely resistant to anti-coagulant and/or anti-platelet therapies. Inhibition of the common terminal complement pathway by Eculizumab prevents the frequently occurring thrombotic events responsible for the high mortality and morbidity observed in patients not treated with anti-complement therapy. While many in vitro and ex vivo studies elaborate numerous different molecular interactions between complement activation products and hemostasis, this review focuses on the clinical evidence that links these two fields in humans. Several non-infectious conditions with known complement involvement are scrutinized for common patterns concerning a prothrombotic statues and the occurrence of certain complement activation levels. Next to PNH and aHUS, germline encoded CD59 or CD55 deficiency (the latter causing the disease Complement Hyperactivation, Angiopathic thrombosis, and Protein-Losing Enteropathy; CHAPLE), autoimmune hemolytic anemia (AIHA), (catastrophic) anti-phospholipid syndrome (APS, CAPS) and C3 glomerulopathy are considered. Parallels and distinct features among these conditions are discussed against the background of thrombosis, complement activation, and potential complement diagnostic and therapeutic avenues.

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Nutraceutical Potential of Leaf Hydro-Ethanolic Extract of the Edible Halophyte Crithmum maritimum L.

Molecules ◽

10.3390/molecules26175380 ◽

2021 ◽

Vol 26 (17) ◽

pp. 5380

Author(s):

Aymen Souid ◽

Clara Maria Della Croce ◽

Stefania Frassinetti ◽

Morena Gabriele ◽

Luisa Pozzo ◽

...

Keyword(s):

Pathogenic Bacteria ◽

Antioxidant Activities ◽

Ex Vivo ◽

Biological Effects ◽

Ethanolic Extract ◽

Coastal Dunes ◽

Total Phenolic ◽

Alcoholic Extract ◽

Beneficial Effects

Aromatic halophytes represent an exceptional source of natural bioactive compounds for the food industry. Crithmum maritimum L., also known as sea fennel, is a halophyte plant colonizing cliffs and coastal dunes along Mediterranean and Atlantic coasts. It is well known to produce essential oils and polyphenols endowed with antioxidant and biological effects. The present work reports the phytochemical profile, as well as antioxidant, antimicrobial and antimutagenic properties of C. maritimum leaf hydro-alcoholic extract. From LC-ESI-MS analysis, eighteen phenolic compounds were depicted in sea fennel extract and the amount of total phenolic content exceeds 3% DW. Accordingly, C. maritimum extract showed strong antioxidant activities, as evidenced by in vitro (DPPH, ORAC, FRAP) and ex vivo (CAA-RBC and hemolysis) assays. An important antimicrobial activity against pathogenic strains was found as well as a strong capacity to inhibit Staphylococcus aureus (ATCC 35556) biofilm formation. Sea fennel extracts showed a significant decrease of mutagenesis induced by hydrogen peroxide (H2O2) and menadione (ME) in Saccharomyces cerevisiae D7 strain. In conclusion, our results show that C. maritimum is an exceptional source of bioactive components and exert beneficial effects against oxidative or mutagenic mechanisms, and pathogenic bacteria, making it a potential functional food.

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