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Immunologically Mediated Diseases and Allergic Reactions
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Kim A. Campbell, Caroline C. Whitacre
The second class of mediators released by activated mast cells are the newly formed mediators. Generation of lipid mediators begins with the activation of the enzyme phospholipase A2, which catalyzes the release of arachidonic acid from the membrane phospholipids. Arachidonic acid is then sequentially metabolized by the enzymes in one of two separate pathways: the cyclooxygenase pathway that produces the prostaglandins or the 5-lipoxygenase pathway that forms the leukotrienes. During allergic reactions, prostaglandin D2 induces vasodilation and bronchoconstriction. The leukotrienes C4, D4, and E4, previously referred to as slow-reacting substance of anaphylaxis, mediate prolonged bronchoconstriction, vasopermeability, and mucus secretion. Another derivative of phospholipid is platelet activating factor, which aggregates platelets, leading to microthrombi. Platelet activating factor also causes severe bronchoconstriction, increases vasopermeability, and augments chemotaxis of neutrophils. Whereas mast cells have been shown to produce prostaglandin D2, the leukotrienes, and PAF, basophils apparently synthesize only the leukotrienes (See chapter 4).
Anaphylaxis
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Arachidonic acid metabolites derived from membrane phospholipids generate pro-inflammatory mediators such as cysleukotrienes (CysLTs), prostaglandins and PAF that can be released during anaphylaxis. Studies have shown that circulating levels of leukotrienes (LTB4, LTC4, and LTD4) increase during anaphylaxis, and are involved in enhanced vascular permeability and bronchoconstriction (Reber et al. 2017). Prostaglandin D2 (PGD2), also released from activated mast cells, promotes vasodilation, vasopermeability and airway smooth muscle bronchoconstriction (Hardy et al. 1984). The role of PAF in anaphylaxis in humans is still not well defined, however studies suggest that PAF and platelet-activating factor acetylhydrolase (PAF-AH) activity are increased in anaphylaxis, and that PAF-AH is inversely correlated with anaphylaxis severity (Vadas et al. 2013).
Other Sleep Modulators
Published in Shojiro Inoué, Biology of Sleep Substances, 2020
Some additional information should be referred to here. VIP is regarded as an energy-mobilizing hormone. The plasma VIP level is known to increase during and after muscular exercise.46 Plasma VIP significantly increased after a 30-min ergometer exercise test in young men who had undergone 5-d sleep deprivation in combination with prolonged strain and energy deficiency.47 The feeling of sleepiness or an elevated demand for sleep after exercise might be partly accounted for by the rise in the plasma level of VIP, if VIP can cross the blood-brain barrier and affect the neural activity in the central nervous system. Shimatsu et al.48 reported that the release of VIP was stimulated by the presence of prostaglandin D2, a potent sleep inducer (see Chapter 6). A definite circadian rhythm was found in the cerebrospinal fluid (CSF) level of VIP in monkeys, with a peak in the early dark period and a nadir in the early light period.49 Finally, VIP is reportedly correlated to the immune system,50 suggesting interactions with immunomodulatory somnogens.51
Autoantibodies in Pandemrix®-induced narcolepsy: Nine candidate autoantigens fail the conformational autoantibody test
Published in Autoimmunity, 2019
Madeleine Wallenius, Alexander Lind, Omar Akel, Emma Karlsson, Markus Svensson, Elin Arvidsson, Anita Ramelius, Carina Törn, Lars Palm, Åke Lernmark, Helena Elding Larsson
Other suggested NT1 autoantigens include Tribbles homologue 2 (TRIB2) [17–20], α-melanocyte stimulating hormone (α-MSH) [21], Prostaglandin D2 Receptor DP1 (DP1) [22], methyltransferase-like 22 (METTL22) and 5′-nucleotidase cytosolic 1A (NT5C1A) [23]. The suggestions of non-hypocretin neuron-specific autoantigens are of interest when considering alternative pathogenic mechanisms behind NT1 as opposed to a direct immune-attack against these cells. Both α-MSH and DP1 have known implications to NT1-associated side-effects. α-MSH is presumed to be involved in weight homeostasis by inhibiting feeding behaviour [24]. NT1 patients are known to have a higher risk to develop obesity and other metabolic problems associated with the loss of hypocretin neurons [25]. Among its many functions in the central nervous system, DP1 is known to be involved in the regulation of sleep through its activation by prostaglandin D2, a sleep-promoting substance [22].
Investigational drugs targeting prostaglandin receptors for the treatment of glaucoma
Published in Expert Opinion on Investigational Drugs, 2018
Artemis Matsou, Eleftherios Anastasopoulos
Prostaglandin D2 (PGD2) elicits its responses by activating one of the two receptors DP1 or DP2. Although largely involved in ocular immune responses, DP receptor agonists were also found to have significant IOP lowering effect in animal studies [66,67]. The selective synthetic DP prostaglandin receptor agonist, BW 245C was reported to lower IOP in rabbits, however when tested in humans, it produced intense acute conjunctival hyperemia [68] and has since been abandoned due to its side effects. Similar results were found for other DP prostaglandin agonists such as SQ-27986 [69], BW 572C85, and BW 192C86. AL–6598, the isopropyl ester prodrug of AL-6556, is a DP/EP2 receptor agonist that was shown to produce a 53% IOP drop in cynomolgus monkeys in a twice daily regime [70], while in humans resulted in a sustained reduction in IOP of more than 27% [71]. Significant conjunctival hyperemia was again noted but with no signs of intraocular inflammation. Another study in normotensive monkey eyes by Torris et al., demonstrated that AL-6598, has a dual effect on aqueous humor dynamics; both an increase in aqueous humor production, which is an undesired consequence, and an increase in aqueous humor drainage via the uveoscleral pathway [71]. Since then, there is a paucity of data and new research in DP agonists for glaucoma, and quite reasonably so, since more potent molecules with fewer side effects have come to light.
Moving toward consensus on diagnosis and management of severe asthma in adults
Published in Current Medical Research and Opinion, 2018
Daniel Colodenco, Oscar Palomares, Carlos Celis, Alan Kaplan, Christian Domingo
As described earlier, eosinophils are known major inflammatory cells involved in the pathophysiology of asthma. These also play a role in airway remodeling through production and expression of several fibrogenic factors, particularly transforming growth factor (TGF)-β157. The cytokine IL-5 primarily drives eosinophil proliferation, maturation, activation, and survival, which are associated with severe, difficult-to-treat asthma58. Furthermore, IL-13 stimulates eosinophilic airway inflammation and promotes mucus metaplasia, subepithelial fibrosis, and airway remodeling59. While in the lung, eosinophils stimulate secretion of cytokines (IL-13 IL-5, TGF-β, and osteopontin), chemokines (CCL-11, CCL22, matrix metalloproteinases [MMPs] and granule mediators [e.g. erythropoietin and major basic protein]), and leukotrienes (LTC4 and LTB4)60. Recently, prostaglandin D2 (PGD2) has been shown to play a vital role in mediating eosinophilic airway inflammation in asthma through stimulation of Th2 cell migration, delayed Th2 cell apoptosis, and production of IL-4, IL-5, and IL-1361. Periostin, a matricellular protein, has also been implicated in eosinophil recruitment62.