Rupatadine protects against pulmonary fibrosis by attenuating PAF-mediated senescence in rodents

• Published in: PloS one Vol. 8; no. 7; p. e68631
• Main Authors: Lv, Xiao-xi, Wang, Xiao-xing, Li, Ke, Wang, Zi-yan, Li, Zhe, Lv, Qi, Fu, Xiao-ming, Hu, Zhuo-wei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.07.2013; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Attenuation; Autophagy; Bleomycin; Cellular Senescence - drug effects; Chronic obstructive pulmonary disease; Collagen; Cyproheptadine - analogs & derivatives; Cyproheptadine - pharmacology; Cyproheptadine - therapeutic use; Cytokines; Effectiveness; Fibrosis; Health aspects; Histamine; Immune response; Immune system; Immunology; Infiltration; Inflammation; Laboratory animals; Lung - drug effects; Lung - pathology; Lung diseases; Male; Mesenchyme; Mice; Mice, Inbred C57BL; p53 Protein; Pathogenesis; Pharmacology; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - metabolism; Platelet Activating Factor - physiology; Platelet Membrane Glycoproteins - antagonists & inhibitors; Platelet-activating factor; Pulmonary fibrosis; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - prevention & control; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - antagonists & inhibitors; Respiratory function; Rodents; Senescence; Silica; Silicon dioxide; Silicosis; Studies; Transformation; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Protein p53 - physiology; Beijing China; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068631

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.