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Epithelial Function and Airway Responsiveness
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Roy G. Goldie, Janet M. H. Preuss
The precise mechanism(s) responsible for asthma-associated airway epithelial damage have not been completely elucidated. However, a significant contribution from the cytotoxic products of eosinophils, notably major basic protein (MBP), has been proposed.201 In asthma, eosinophils are recruited into the airways and can be detected in the epithelial layer.70,187 Currently, it is believed that eosinophils play a critical role in the pathogenesis of asthma, and a correlation between eosinophil number and the changes in pulmonary function has been reported.202 MBP can induce airway epithelial damage that is histologically similar to that observed in asthma.54,188,201,203 Perhaps importantly, this damage has been associated with increased responsiveness of isolated airway tissues.204,205
Pharmacological and Biochemical Changes in Airway Smooth Muscle in Relation to Bronchial Hyperresponsiveness
Published in Devendra K. Agrawal, Robert G. Townley, Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Allergic mediators could be a cause of allergen-induced airway smooth muscle alterations; other cell products released during the allergic response could also play a role. Thus, it was recently demonstrated that major basic protein (MBP), which is released from eosinophils in patients with asthma,186,187 may cause hyperresponsiveness of guinea pig respiratory smooth muscle in vitro by inhibiting the function of epithelial but not smooth muscle cells.188 It is known that MBP is cytotoxic for epithelial cells,189 and epithelial cell damage could cause reduced release of epithelium-derived relaxing factor (EpDRF).20,188
Regulation of Eosinophil Mediator Release by Adhesion Molecules
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Major basic protein consists of a single polypeptide chain of 117 amino acids; it is rich in arginine, has a molecular mass of 14 kD, and has a calculated isoelectric point of 10.9 (1). Major basic protein shows a variety of activities on non-mammalian and mammalian cells. For example, purified MBP damages schistosomula of S. mansoni (2). When eosinophils were incubated with schistosomula in the presence of antibody against S. mansoni, MBP was released and deposited on the surface of the parasites (3). Major basic protein also damages other parasites, such as Trichinella spiralis and Brugia pahangi (4,5). Major basic protein is toxic to human epithelial cells (6) and causes ciliostasis and exfoliation of respiratory epithelial cells (7); this latter effect mimics the pathology of asthma (8). Major basic protein augments contraction of the tracheal smooth muscle induced by acetylcholine in vitro (9), and inhalation of MBP causes bronchial hyperresponsiveness in primates (10). Interestingly, incubation of human peripheral blood leukocytes with MBP causes a dose-dependent release of histamine that is calcium-, temperature-, and energy-dependent, suggesting non-cytotoxic activation of basophils by MBP (11). Similarly, MBP activates mediator release from mast cells (11), neutrophils (12), alveolar macrophages (13), platelets (14), and eosinophils themselves (15). Thus MBP is a cytostimulant as well as being cytotoxic to cells.
Reduction/elimination of blood eosinophils in severe asthma: should there be a safety consideration?
Published in Expert Opinion on Biological Therapy, 2022
Konstantinos Katsoulis, Maria Kipourou, Stelios Loukides
Two main types of granules lay next to the bilobed nucleus in the eosinophil cytoplasm: the primary and the secondary or specific granules [8] (Figure 2). Primary granules are filled with galectin-10, the protein responsible for the formation of Charcot-Leyden crystals [12]. The larger secondary granules are entitled to produce and store cationic proteins, chemokines, and cytokines [8,12], which can be immediately and selectively secreted by the uniquely operated the eosinophils mechanism of piecemeal degranulation [8]. Four major proteins, namely major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), with cytotoxic, neurotoxic, antimicrobial, and antiviral properties, are the components of the specific granule core and matrix [8,17]. These basic proteins contained in the eosinophil granules are the ones binding with the acidophilic stain eosin and giving the eosinophils their characteristic appearance under microscopic examination and subsequently their name.
Eosinophil exocytosis in a poorly differentiated tubular gastric adenocarcinoma: case report
Published in Ultrastructural Pathology, 2022
Rosario Caruso, Eleonora Irato, Luciana Rigoli
Eosinophils may eliminate target tumor cells in vitro by releasing cytotoxic proteins, such as granzyme A, cationic proteins (major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase), and multiple cytokines including TNF, IFN, and IL-18, and 33.9,10,30,31 Accordingly, our ultrastructural study shows that eosinophils are in intimate contact with undamaged or dying tumor cells. These tumor cells exhibited various degrees of cell injury ranging from mitochondrial swelling, dilation of the nuclear envelope up to cytoplasmic vacuoles, and nuclear chromatin condensation, but without margination of chromatin. These morphological changes are similar to those reported in paraptosis, a non-apoptotic form of programmed cell death, characterized by a vacuolization process that starts with dilatation of the endoplasmic reticulum and the mitochondria.32 Electron microscope is a useful tool to identify various types of cell death.33 Paraptosis can be distinguished from other types of cell deaths such as apoptosis, autophagic cell death, as well as necrosis, according to ultrastructural morphologies such as chromatin condensation and margination (present in apoptosis), accumulation of autophagic vacuoles containing intracellular content (as observable in autophagic cell death), cytoplasmic swelling, and rupture of plasma membrane (necrosis).33
Comparison of serum eosinophil-derived neurotoxin levels between wheezing and non-wheezing groups in children with respiratory tract infection
Published in Journal of Asthma, 2020
Hanna Kim, Grace-Eunmi Kwon, Young-Ho Kim, Zak Callaway, Yu-Sok Han, Jacky Jeong-Koo Seo, Fuyong Jiao, Chang-Keun Kim
Eosinophilic granules are attached to the cell membrane and contain strongly positive charged protein substances that cause tissue damage in these granules (5–7). Major basic protein (MBP) is at the center of the granule, while eosinophilic cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil-derived neurotoxin (EDN), are found in the substrate of the granule. Among these granular proteins, EDN has been attracting much attention as a useful biomarker for diagnosis and monitoring of asthma, and it is associated with recurrent wheezing, pediatric asthma, allergic rhinitis, and chronic cough in children after bronchiolitis (8). According to previous studies, eosinophil counts or percentages in blood do not accurately reflect eosinophil activity; they are merely a measure of eosinophil presence in the fluid tested. In contrast, measurement of the eosinophilic granular proteins EDN and ECP has been reported to accurately reflect a substantial degree of eosinophilic inflammatory response (9,10).