A vitamin E long-chain metabolite and the inspired drug candidate α-amplexichromanol relieve asthma features in an experimental model of allergen sensitization. (July 2022)

• Record Type: Journal Article
• Authors: Cerqua, Ida; Neukirch, Konstantin; Terlizzi, Michela; Granato, Elisabetta; Caiazzo, Elisabetta; Cicala, Carla; Ialenti, Armando; Capasso, Raffaele; Werz, Oliver; Sorrentino, Rosalinda; Seraphin, Denis; Helesbeux, Jean-Jacques; Cirino, Giuseppe; Koeberle, Andreas; Roviezzo, Fiorentina; Rossi, Antonietta
• Is Part Of: Pharmacological research. Volume 181(2022)
• Publication Date: 2022-07
• Subjects: 5-LOX 5-lipoxygenase -- 12-HHT (12(S)-hydroxyheptadecatrienoic acid; -- α-T-13′-COOH α-13′-carboxychromanol -- α-AC α-amplexichromanol -- AA arachidonic acid -- AHR airway hyperreactivity -- COX cyclooxygenase -- HETE hydroxyeicosatetraenoic acid -- DHA docosahexaenoic acid -- EPA eicosapentaenoic acid -- ELISA enzyme-linked immunosorbent assay -- H&E Hematoxylin and eosin -- IL interleukin -- LTs leukotrienes -- LM lipid mediator -- LCMs long-chain metabolites -- OVA ovalbumin -- PUFA polyunsaturated fatty acids -- SPM specialized pro-resolving mediators -- T tocopherol -- TX thromboxane; in this article α-13′-carboxychromanol (PubChem CID: 53481461) -- carbachol (PubChem CID: 5831) -- dimethyl sulfoxide (PubChem CID: 679) -- ovalbumin (PubChem CID: 71311993); α-13′-carboxychromanol -- α-amplexichromanol -- Vitamin E -- Bronchial hyperreactivity -- Cyclooxygenase -- Lipoxygenase; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106250
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Benefits for vitamin E intake in diseases with inflammatory components have been described and related in part, to endogenously formed metabolites (long-chain metabolites, LCM). Here, we have evaluated the role of LCM in relieving asthma features. To this aim, the endogenous vitamin E metabolite α-13′-carboxychromanol (α-T-13′-COOH) that acts as potent 5-lipoxygenase inhibitor has been administered either intraperitoneally or by oral gavage to BALB/c mice sensitized by subcutaneous injection of ovalbumin (OVA). We also have taken advantage of the metabolically stable α-T-13′-COOH derivative α-amplexichromanol (α-AC). Intraperitoneal treatment with α-T-13'-COOH reduced OVA-induced airway hyperreactivity (AHR) as well as peri-bronchial inflammatory cell infiltration. α-AC was more efficacious than α-T-13'-COOH, as demonstrated by better control of AHR and in reducing subepithelial. Both compounds exerted their protective function by reducing pulmonary leukotriene C4 levels. Beneficial effects of α-AC were coupled to inhibition of the sensitization process, as indicated by a reduction of IgE plasma levels, lung mast cell infiltration and Th2 immune response. Metabololipidomics analysis revealed that α-AC raises the pulmonary levels of prostanoids, their degradation products, and 12/15-lipoxygenase metabolites. Following oral administration, the pharmacodynamically different profile in α-T-13′-COOH and α-AC was abrogated as demonstrated by a similar and improved efficacy in controlling asthma features as well as by metabololipidomics analysis. In conclusion, this study highlights a role for LCM and of vitamin E derivatives as pharmacologically active compounds that ameliorate asthmatic features and defines an important role for endogenous vitamin E metabolites in regulating immune response underlying the sensitization process. Graphical Abstract: ga1 Highlights: Vitamin E long-chain metabolites relieve allergen-induced bronchial hyperreactivity. Vitamin E long-chain metabolites inhibit Th2 immune response induced by allergen. Vitamin E long-chain metabolites modulate anti- and pro-inflammatory lipid mediators