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Complement Activation: Challenges to Nanomedicine Development
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Dennis E. Hourcade, Christine T. N. Pham, Gregory M. Lanza
Complement activation is mediated by three major pathways (Fig. 9.1) [3, 4]. Each pathway responds to a different set of activators, ensuring that a wide range of dangerous agents are recognized: The classical pathway (CP) is triggered by antibody: antigen complexes, and the lectin pathway (LP) responds to specific carbohydrate moieties. The alternative pathway (AP) operates spontaneously at low levels and is further activated by a range of microbial surfaces. Each activation pathway results in the assembly of the C3 convertases, the central enzymes of the C cascade, which cleave the fluid phase protein C3, producing C3a and C3b. Nascent C3b can bind covalently to the target surface and mediate clearance by the mononuclear phagocytic system (MPS). Target-bound C3b can amplify C activity by providing an assembly point for additional AP convertases (the amplification loop). C3b can also form a complex with preformed C3 convertase to generate C5 convertase, a protease that cleaves C5 into C5a and C5b. C5b initiates the complement terminal pathway, culminating in the assembly of the membrane attack complex (MAC) in the plasma membrane. The MAC promotes cell lysis by disrupting membrane integrity. C3a and C5a, the anaphylatoxins, recruit immune cells that promote further inflammatory reactions [5, 6]. C3d, a C3 derivative, in complex with antigen, provides an adjuvant effect leading to the generation of higher antibody titer [7].
Short-term exposure of female BALB/cJ mice to e-cigarette aerosol promotes neutrophil recruitment and enhances neutrophil-platelet aggregation in pulmonary microvasculature
Published in Journal of Toxicology and Environmental Health, Part A, 2023
Hunter T. Snoderly, Hassan Alkhadrawi, Dhruvi M. Panchal, Kelly L. Weaver, Jenna N. Vito, Kasey A. Freshwater, Stell P. Santiago, I. Mark Olfert, Timothy R. Nurkiewicz, Margaret F. Bennewitz
The findings that circulating sICAM-1 and C5a are significantly increased after EC exposure may aid in explaining why neutrophilia occurred in the lung vasculature. Elevated levels of sICAM-1 were detected following a single session of e-cigarette use in naïve subjects, and are a known marker of inflammation and endothelial damage (Chatterjee et al. 2021), which may drive initial neutrophil recruitment. C5a, in addition to its role in the complement response, also aids in neutrophil chemoattraction (Guo and Ward 2005). In addition, SDF-1, KC, and TIMP-1 are all known to play a role in neutrophil chemoattraction with the latter two also involved in NETosis (De Filippo et al. 2013; Snoderly et al. 2022). However, EC-induced changes in the expression of each of these was not significant, suggesting EC-induced cytokine release did not markedly influence neutrophils via these mechanisms. Further, because these cytokines were measured in plasma isolated from whole blood, additional work is needed to confirm whether such changes occur specifically in the lung.