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      Air Bubbles Activate Complement and Trigger Hemostasis and C3-Dependent Cytokine Release Ex Vivo in Human Whole Blood

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          Key Points

          • Air bubbles trigger a C3-driven thromboinflammation in human whole blood.

          • Blocking C3, but not C5, attenuates the air-induced inflammation.

          • Avoiding ambient air in test tubes attenuates thromboinflammation.

          Abstract

          Venous air embolism, which may complicate medical and surgical procedures, activates complement and triggers thromboinflammation. In lepirudin-anticoagulated human whole blood, we examined the effect of air bubbles on complement and its role in thromboinflammation. Whole blood from 16 donors was incubated with air bubbles without or with inhibitors of C3, C5, C5aR1, or CD14. Complement activation, hemostasis, and cytokine release were measured using ELISA and quantitative PCR. Compared with no air, incubating blood with air bubbles increased, on average, C3a 6.5-fold, C3bc 6-fold, C3bBbP 3.7-fold, C5a 4.6-fold, terminal complement complex sC5b9 3.6-fold, prothrombin fragments 1+2 (PTF1+2) 25-fold, tissue factor mRNA (TF-mRNA) 26-fold, microparticle tissue factor 6.1-fold, β-thromboglobulin 26-fold (all p < 0.05), and 25 cytokines 11-fold (range, 1.5–78-fold; all p < 0.0001). C3 inhibition attenuated complement and reduced PTF1+2 2-fold, TF-mRNA 5.4-fold, microparticle tissue factor 2-fold, and the 25 cytokines 2.7-fold (range, 1.4–4.9-fold; all p < 0.05). C5 inhibition reduced PTF1+2 2-fold and TF-mRNA 12-fold (all p < 0.05). C5 or CD14 inhibition alone reduced three cytokines, including IL-1β ( p = 0.02 and p = 0.03). Combined C3 and CD14 inhibition reduced all cytokines 3.9-fold (range, 1.3–9.5-fold; p < 0.003) and was most pronounced for IL-1β (3.2- versus 6.4-fold), IL-6 (2.5- versus 9.3-fold), IL-8 (4.9- versus 8.6-fold), and IFN-γ (5- versus 9.5-fold). Antifoam activated complement and was avoided. PTF1+2 was generated in whole blood but not in plasma. In summary, air bubbles activated complement and triggered a C3-driven thromboinflammation. C3 inhibition reduced all mediators, whereas C5 inhibition reduced only TF-mRNA. Combined C5 and CD14 inhibition reduced IL-1β release. These data have implications for future mechanistic studies and possible pharmacological interventions in patients with air embolism.

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          Most cited references50

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          The inflammasome: an integrated view.

          An inflammasome is a multiprotein complex that serves as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of interleukin-1β (IL-1β). Though a number of inflammasomes have been described, the NLRP3 inflammasome is the most extensively studied but also the most elusive. It is unique in that it responds to numerous physically and chemically diverse stimuli. The potent proinflammatory and pyrogenic activities of IL-1β necessitate that inflammasome activity is tightly controlled. To this end, a priming step is first required to induce the expression of both NLRP3 and proIL-1β. This event renders the cell competent for NLRP3 inflammasome activation and IL-1β secretion, and it is highly regulated by negative feedback loops. Despite the wide array of NLRP3 activators, the actual triggering of NLRP3 is controlled by integration a comparatively small number of signals that are common to nearly all activators. Minimally, these include potassium efflux, elevated levels of reactive oxygen species (ROS), and, for certain activators, lysosomal destabilization. Further investigation of how these and potentially other as yet uncharacterized signals are integrated by the NLRP3 inflammasome and the relevance of these biochemical events in vivo should provide new insight into the mechanisms of host defense and autoinflammatory conditions. © 2011 John Wiley & Sons A/S.
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            Microparticles in hemostasis and thrombosis.

            Blood contains microparticles (MPs) derived from a variety of cell types, including platelets, monocytes, and endothelial cells. In addition, tumors release MPs into the circulation. MPs are formed from membrane blebs that are released from the cell surface by proteolytic cleavage of the cytoskeleton. All MPs are procoagulant because they provide a membrane surface for the assembly of components of the coagulation protease cascade. Importantly, procoagulant activity is increased by the presence of anionic phospholipids, particularly phosphatidylserine (PS), and the procoagulant protein tissue factor (TF), which is the major cellular activator of the clotting cascade. High levels of platelet-derived PS(+) MPs are present in healthy individuals, whereas the number of TF(+), PS(+) MPs is undetectable or very low. However, levels of PS(+), TF(+) MPs are readily detected in a variety of diseases, and monocytes appear to be the primary cellular source. In cancer, PS(+), TF(+) MPs are derived from tumors and may serve as a useful biomarker to identify patients at risk for venous thrombosis. This review will summarize our current knowledge of the role of procoagulant MPs in hemostasis and thrombosis.
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              Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients

              Significance The new SARS-CoV-2 pandemic leads to COVID-19 with respiratory failure, substantial morbidity, and significant mortality. Overactivation of the innate immune response is postulated to trigger this detrimental process. The complement system is a key player in innate immunity. Despite a few reports of local complement activation, there is a lack of evidence that the degree of systemic complement activation occurs early in COVID-19 patients, and whether this is associated with respiratory failure. This study shows that a number of complement activation products are systemically, consistently, and long-lastingly increased from admission and during the hospital stay. Notably, the terminal sC5b-9 complement complex was associated with respiratory failure. Thus, complement inhibition is an attractive therapeutic approach for treatment of COVD-19.
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                Author and article information

                Journal
                J Immunol
                J Immunol
                jimmunol
                JI
                The Journal of Immunology Author Choice
                AAI
                0022-1767
                1550-6606
                1 December 2021
                1 December 2021
                : 207
                : 11
                : 2828-2840
                Affiliations
                [* ]Department of Anesthesia and Intensive Care Medicine, Surgical Clinic, Nordland Hospital, Bodø, Norway;
                []Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway;
                []Faculty of Nursing and Health Sciences, Nord University, Bodø, Norway;
                [§ ]Research Laboratory, Nordland Hospital Trust, Bodø, Norway;
                []Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
                []School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St. Lucia, Queensland, Australia;
                [# ]Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway;
                [** ]Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
                [†† ]Faculty of Health Sciences, K.G. Jebsen Thrombosis Research and Expertise Center, UiT The Arctic University of Norway, Tromsø, Norway;
                [‡‡ ]Department of Immunology, Oslo University Hospital and the University of Oslo, Oslo, Norway; and
                [§§ ]Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
                Author notes
                Address correspondence and reprint requests to Benjamin S. Storm, Department of Anesthesia and Intensive Care Medicine, Surgical Clinic, Nordland Hospital Trust, P.O. Box 1480, NO-8092 Bodø, Norway. E-mail address: benjamin.storm@ 123456gmail.com
                Author information
                http://orcid.org/0000-0003-2685-3047
                http://orcid.org/0000-0002-7420-3762
                http://orcid.org/0000-0002-7175-5334
                http://orcid.org/0000-0003-1750-8065
                http://orcid.org/0000-0002-9370-5776
                http://orcid.org/0000-0003-1382-911X
                http://orcid.org/0000-0002-8358-3226
                http://orcid.org/0000-0002-5785-802X
                Article
                ji_2100308
                10.4049/jimmunol.2100308
                8611197
                34732467
                63e6a395-0f4e-415c-b700-37bc9c323319
                Copyright © 2021 by The Authors

                This article is distributed under the terms of the CC BY 4.0 Unported license .

                History
                : 31 March 2021
                : 20 September 2021
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 51, Pages: 14
                Funding
                Funded by: Helse Nord RHF (Northern Norway Regional Health Authority), DOI https://doi.org/10.13039/501100007137;
                Award ID: N/A
                Funded by: The Odd Fellow Foundation;
                Award ID: N/A
                Categories
                Innate Immunity and Inflammation

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