Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.
Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents.
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卢帕他定通过减轻 PAF 介导的啮齿动物衰老来预防肺纤维化
DOI：
10.1371/journal.pone.0068631
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hu ZW
中科院分区：
文献类型：
--
作者：
Lv XX;Wang XX;Li K;Wang ZY;Li Z;Lv Q;Fu XM;Hu ZW
肺纤维化和变应性疾病的发病机制中涉及类似的免疫应答。我们研究了卢帕他定（一种组胺和血小板活化因子（PAF）的双重拮抗剂）对博莱霉素（BLM）和二氧化硅诱导的肺纤维化的潜在治疗效果和机制。在患有博来霉素或二氧化硅诱导的肺纤维化的啮齿动物中给予指定剂量的卢帕他定。通过观察肺组织损伤、纤维化、炎性细胞和细胞因子、肺功能等指标评价卢帕他定的疗效。比较了卢帕他定与H1或PAF受体拮抗剂的抗肝纤维化作用，试图揭示卢帕他定的抗肝纤维化作用机制。卢帕他定以剂量依赖性方式促进肺部炎症和纤维化的消退，如炎症评分、胶原沉积和上皮-间质转化以及纤维化肺组织中炎性细胞或细胞因子的浸润或表达的减少所示。因此，卢帕他定治疗改善了下降的肺功能，并显著降低了动物死亡率。此外，与吡非尼酮、组胺H1拮抗剂氯雷他定或PAF拮抗剂CV-3988相比，卢帕他定不仅能够减轻二氧化硅诱导的矽肺，而且还产生上级疗效。卢帕他定的抗纤维化作用可能与其减弱BLM或PAF诱导的过早衰老有关，因为卢帕他定治疗可防止体内和体外p53/p21依赖性衰老途径的激活。我们的研究表明卢帕他定通过减弱PAF介导的衰老反应促进肺部炎症和纤维化的消退。卢帕他定有望成为治疗肺纤维化这一毁灭性疾病的新药。
A similar immune response is implicated in the pathogenesis of pulmonary fibrosis and allergic disorders. We investigated the potential therapeutic efficacy and mechanism of rupatadine, a dual antagonist of histamine and platelet-activation factor (PAF), in bleomycin- (BLM-) and silica-induced pulmonary fibrosis. The indicated dosages of rupatadine were administered in rodents with bleomycin or silica-induced pulmonary fibrosis. The tissue injury, fibrosis, inflammatory cells and cytokines, and lung function were examined to evaluate the therapeutic efficacy of rupatadine. The anti-fibrosis effect of rupatadine was compared with an H1 or PAF receptor antagonist, and efforts were made to reveal rupatadine’s anti-fibrotic mechanism. Rupatadine promoted the resolution of pulmonary inflammation and fibrosis in a dose-dependent manner, as indicated by the reductions in inflammation score, collagen deposition and epithelial-mesenchymal transformation, and infiltration or expression of inflammatory cells or cytokines in the fibrotic lung tissue. Thus, rupatadine treatment improved the declined lung function and significantly decreased animal death. Moreover, rupatadine was able not only to attenuate silica-induced silicosis but also to produce a superior therapeutic efficacy compared to pirfenidone, histamine H1 antagonist loratadine, or PAF antagonist CV-3988. The anti-fibrotic action of rupatadine might relate to its attenuation of BLM- or PAF-induced premature senescence because rupatadine treatment protected against the in vivo and in vitro activation of the p53/p21-dependent senescence pathway. Our studies indicate that rupatadine promotes the resolution of pulmonary inflammation and fibrosis by attenuating the PAF-mediated senescence response. Rupatadine holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.
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影响因子：
4.4
作者：
de Mello, Luane Marques;Silveira Bechara, Monique Isabel;Rodrigues, Virmondes
通讯作者：
Rodrigues, Virmondes
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
DOI：
10.1016/j.biocel.2007.05.018
发表时间：
2007-01-01
影响因子：
4
作者：
Linge, Annett;Weinhold, Karina;Barth, Kathrin
通讯作者：
Barth, Kathrin
影响因子：
4.4
作者：
Mi, Su;Li, Zhe;Hu, Zhuo-Wei
通讯作者：
Hu, Zhuo-Wei
影响因子：
14.2
作者：
Holgate, Stephen T.;Peters-Golden, Marc;Henderson, William R., Jr.
通讯作者：
Henderson, William R., Jr.