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

PLoS One. 2013 Jul 15;8(7):e68631. doi: 10.1371/journal.pone.0068631. Print 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Senescence / drug effects
  • Cyproheptadine / analogs & derivatives*
  • Cyproheptadine / pharmacology
  • Cyproheptadine / therapeutic use
  • Lung / drug effects
  • Lung / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Platelet Activating Factor / antagonists & inhibitors
  • Platelet Activating Factor / metabolism
  • Platelet Activating Factor / physiology*
  • Platelet Membrane Glycoproteins / antagonists & inhibitors
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / prevention & control*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • Tumor Suppressor Protein p53
  • platelet activating factor receptor
  • rupatadine
  • Cyproheptadine

Grant support

This study was supported by grants from the National Natural Science Foundation (81273529), Major Program of National Natural Science Foundation (81030056), International Corporation Project supported by the Ministry of Science and Technology (2010DFB32900), program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, No.IRT1007), and Creation of Major New Drugs (2009ZX09301-003-13), Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (NO. BZ0150). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.