1. IBPA a mutual prodrug of ibuprofen and acetaminophen alleviates inflammation, immune dysregulation and fibrosis in preclinical models of systemic sclerosis.
- Author
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Rodrigues de Almeida A, Jaime Bezerra Mendonça Junior F, Tavares Dantas A, Eduarda de Oliveira Gonçalves M, Chêne C, Jeljeli M, Chouzenoux S, Thomas M, David de Azevedo Valadares L, Andreza Bezerra Correia M, Ângela da Silva Alves W, Carvalho Lira E, Doridot L, Jesus Barreto de Melo Rêgo M, Cristiny Pereira M, Luzia Branco Pinto Duarte A, Saes Parra Abdalla D, Nicco C, Batteux F, and Galdino da Rocha Pitta M
- Subjects
- Animals, Humans, Female, Mice, Male, Middle Aged, Inflammation drug therapy, Cells, Cultured, Skin drug effects, Skin pathology, Skin immunology, Hypochlorous Acid, Adult, Prodrugs therapeutic use, Prodrugs pharmacology, Mice, Inbred BALB C, Acetaminophen pharmacology, Scleroderma, Systemic drug therapy, Scleroderma, Systemic immunology, Scleroderma, Systemic pathology, Ibuprofen therapeutic use, Ibuprofen pharmacology, Cytokines metabolism, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Fibrosis drug therapy, Disease Models, Animal
- Abstract
Systemic sclerosis (SSc) is a devastating autoimmune illness with a wide range of clinical symptoms, including vascular abnormalities, inflammation, and persistent and progressive fibrosis. The disease's complicated pathophysiology makes it difficult to develop effective therapies, necessitating research into novel therapeutic options. Molecular hybridization is a strategy that can be used to develop new drugs that act on two or multiple targets and represents an interesting option to be explored for the treatment of complex diseases. We aimed to evaluate the effects of a hybrid mutual prodrug of ibuprofen and acetaminophen (IBPA) in peripheral blood mononuclear cells (PBMC) isolated from SSc patients, and in an in vivo model of SSc induced in BALB/c mice by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. The mice were treated at the same time with daily intraperitoneal injections of IBPA (40 mg/kg). Pulmonary and skin fibrosis as well as immune responses were evaluated. IBPA significantly decreased the release of cytokines in PBMC culture supernatants from SSc patients after stimulation with phytohemagglutinin-M (IL-2, IL-4, IL-6, IL-10, IL-13, IL-17A, TNF and IFN-γ).In HOCl-induced SSc, IBPA treatment prevented dermal and pulmonary fibrosis, in addition to reducing CD4 + T and B cells activation and reversing the M2 polarization of macrophages in spleen cells, and inhibiting IFN-γ secretion in splenocyte cultures. These results show the anti-inflammatory and antifibrotic effects of IBPA in SSc and highlight the therapeutic potential of this mutual prodrug, providing support for future studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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