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.
摘要：
系统性硬化症（SSc）是一种毁灭性的自身免疫性疾病，具有广泛的临床症状，包括血管异常,炎症,和持续性和进行性纤维化。这种疾病复杂的病理生理学导致难以开发有效的治疗方法,需要研究新的治疗方案。分子杂交是一种策略，可用于开发作用于两个或多个靶标的新药，并代表了一种有趣的选择，可用于治疗复杂疾病。我们旨在评估布洛芬和对乙酰氨基酚（IBPA）的混合相互前药在SSc患者外周血单核细胞（PBMC）中的作用，并且在BALB/c小鼠中通过皮内注射次氯酸(HOCl)6周诱导的SSc的体内模型中。在每天腹膜内注射IBPA(40mg/kg)的同时处理小鼠。评估肺和皮肤纤维化以及免疫反应。用植物血凝素-M（IL-2，IL-4，IL-6，IL-10，IL-13，IL-17A，TNF和IFN-γ)。在HOCl诱导的SSc中，IBPA治疗可预防皮肤和肺纤维化，除了减少CD4+T和B细胞活化和逆转脾细胞中巨噬细胞的M2极化外，并抑制脾细胞培养物中IFN-γ的分泌。这些结果表明了IBPA在SSc中的抗炎和抗纤维化作用，并突出了这种共同前药的治疗潜力，为未来的研究提供支持。
