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Complement-Mediated Lipopolysaccharide Release
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Activation of the complement cascade sets in motion a series of events that (1) facilitate the extravasation of mononuclear phagocytes into areas of infection, (2) destroy invading microorganisms by opsonization or by direct MAC-mediated membrane damage, and (3) clear the blood of antigens such as bacteria and bacterial debris by routing C3b-bound antigens to the liver and spleen for ingestion by hepatic and splenic macrophages. Anaphylatoxins, the low molecular weight split products C3a, C4a, and C5a, act on mast cells and basophils to release histamine and other inflammatory mediators, increasing vasopermeability and vasodilation. C5a is also a potent chemotactic agent, facilitating the extravasation of neutrophils into inflamed tissue. Mononuclear phagocytes possess receptors for C3b and C4b and will readily bind, internalize, and degrade microorganisms coated with these complement proteins (9). Human erythrocytes also possess receptors for C3b, and erythrocyte binding to C3b-coated particulate antigens or immune complexes is important in clearing antigen from the bloodstream (1). Finally, as discussed above, under the appropriate circumstances, the MAC mediates direct bacteriolysis. Thus, although the biological properites of activated complement components are legion (Table 1), the proteins are designed to recognize and eliminate infectious agents, foreign particles, or altered self molecules.
Acute Alveolar Injury: Experimental Models
Published in Joan Gil, Models of Lung Disease, 2020
Several subsequent clinical studies have clearly demonstrated that the plasma of most patients following massive trauma, major abdominal surgery, acute pancreatitis, disseminated intravascular coagulation, burns or septic shock contains elevated levels of C5a (Duchateau et al., 1984; Weinberg et al., 1984). Only one group has reported a sufficiently high correlation between elevated plasma C5a and the development of acute lung injury in these patients to suggest a predictive value in the plasma C5a level (Hammerschmidt et al., 1980). Others have concluded that serum complement activation is probably a necessary but not sufficient condition for the development of acute lung injury (Duchateau et al., 1984) while still others have questioned whether intravascular complement activation plays any significant role in the pathogenesis of ARDS. These doubts have been based upon the finding of substances chemotactic for neutrophils in alveolar lavage fluid but not in the plasma of patients with ARDS (Fowler et al., 1987).
The Pituitary Gland, Psychoneuroimmunology and Infection
Published in Herman Friedman, Thomas W. Klein, Andrea L. Friedman, Psychoneuroimmunology, Stress, and Infection, 2020
Istvan Berczi, Andor Szentivanyi
Sepsis and endotoxin shock are characterized by diffuse intravascular coagulation, complement activation by both pathways and the release of immunosuppressive hormones and cytokines. Systemically released C3a and C5a is immunosuppressive and may impair chemotaxis. The activation of neutrophilic granulocytes and other phagocytic cells by complement split products in the circulation may lead to vascular damage, increased permeability with edema, impaired microvascular flow, and ultimately contribute to multiorgan failure. Basophils, mast cells and platelets also release cytokines and biologically active substances under these conditions, which may further aggravate the situation. The production of IL-1, IL-2 and IFN-γ is depressed, whereas PGE2 levels are excessively elevated throughout the course of disease. TNF is detectable with equal frequency in patients with shock from gram-negative or gram-positive bacillary sepsis and its level is highest in the initial stage and decreasing significantly over the subsequent 24 hr.
C5a Serum Levels in Patients with Endometriosis: A Cross-Sectional Study
Published in Immunological Investigations, 2023
Danilo Rahal, Carlos Bezerra Sobrinho, Laura Vilas Boas, Cesar Augusto Capellari, Fabiana Antunes Andrade, Renato Nisihara
The serum C5a concentrations are increased in inflammatory and autoimmune diseases according to recent publications (Ajona et al. 2019; Nothnick 2001; Quadros and Cunha 2016). In addition, the endometriotic cells in the peritoneal cavity can initiate inflammatory responses, increasing vasodilation and increasing permeability of blood vessels (Králíčková et al. 2018), potentially contributing to the high C5a levels observed in patients with EM. Thus, C5a may participate in an immune response in the EM by stimulating the production of inflammatory mediators and recruiting inflammatory cells (Guo and Ward 2005). However, it is not clear if higher C5a levels are a result of EM or a contributing factor. There are no studies evaluating C5a in peritoneal fluid in patients with endometriosis.
C5 inhibitors are not C5a inhibitors
Published in Expert Review of Anti-infective Therapy, 2023
Endry H.T. Lim, Alexander P.J. Vlaar, Sanne de Bruin, Matthijs C. Brouwer, Diederik van de Beek
Furthermore, the authors state that the use of C5 inhibitors was associated with a similar risk of serious adverse events (SAEs) and did not increase the risk of infection. However, C5 inhibition in COVID-19 has been associated with an increased risk of infection [2]. In the study by Annane [8], eculizumab treatment in COVID-19 patients led to significantly higher rate of infectious complications including ventilator-associated pneumonia, despite prophylactic antibiotics against meningococcal infection. Recent results of a phase 3 randomized controlled trial (NCT04369469) investigating the effects of ravulizumab in severe COVID-19 patients showed a higher incidence of infections and infestations in the treated group, compared to the control group. Another advantage of specifically inhibiting C5a over C5 and upstream inhibitors is that C5a inhibition does not affect MAC formation and is not associated with increased risk of infection [6,7]. In conclusion, C5 and C5a inhibitors should not be considered to have a similar mechanism of action and effectivity.
The efficacy and safety of complement C5a inhibitors for patients with severe COVID-19: a systematic review and meta-analysis
Published in Expert Review of Anti-infective Therapy, 2023
Chi-Lun Tsai, Chih-Cheng Lai, Ching-Yi Chen, Ho-Sheng Lee
Besides the clinical benefits of C5a inhibitors, this study also evaluated the safety of C5a inhibitors for the treatment of patients with severe COVID-19. We found that the use of C5a inhibitors was associated with a similar risk of serious AEs and acute kidney injury to the control group. We also found that C5a inhibitors did not increase the risk of infection. These findings were consistent with previous studies [36,37]. In the phase 2 trial, infections (including Staphylococcal infection) were reported in 20% (3/15) of patients receiving vilobelimab, which was lower than in the control group (33%, 5/15) [37]. Vlaar et al. also reported a similar proportion of bacterial infections across the study and control groups (68 [39%] vs 75 [40%]) [36]. Finally, the risk of discontinuation of the study drug due to any AE was similar between the study group and control group (5 [3%] vs 3 [2%]) in one RCT [36]. All these findings indicated that C5a inhibitors were tolerable in the treatment of patients with severe COVID-19.