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Pulm Pharmacol Ther. 2014 Feb;27(1):17-28. doi: 10.1016/j.pupt.2013.03.003. Epub 2013 Mar 19.

NO-releasing xanthine KMUP-1 bonded by simvastatin attenuates bleomycin-induced lung inflammation and delayed fibrosis.

Author information

  • 1Department of Cardiology, Yuan's General Hospital, Kaohsiung, Taiwan.
  • 2Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 3Department of Pathology, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 4Department of Anatomy, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 5Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 6Department of Pharmacology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: ingjun@kmu.edu.tw.



Pulmonary fibrosis (PF) is a progressing lung injury initiated by pulmonary inflammation (PI). Bleomycin (BLM) is the most common pathogenesis of PF through early PI and extensive extracellular matrix deposition. This study is aimed to determine whether NO-releasing KMUP-1 inhibits PI and PF, and if so, the benefits of KMUP-1S resulted from simvastatin (SIM)-bonding to KMUP-1.


C57BL/6 male mice were intra-tracheally administered BLM (4 U/kg) at day 0. KMUP-1 (1-5 mg/kg), KMUP-1S (2.5 mg/kg), SIM (5 mg/kg), Plus (KMUP-1 2.5 mg/kg + SIM 2.5 mg/kg), and clarithromycin (CAM, 10 mg/kg) were orally and daily administered for 7 and 28 days, respectively, to mice, sacrificed at day-7 and day-28 to isolate the lung tissues, for examining the inflammatory and fibrotic signaling and measuring the cell population and MMP-2/MMP-9 activity in broncholaveolar lavage fluid (BAL).


KMUP-1 and KUP-1S significantly decreased neutrophil counts in BAL fluid. Fibroblastic foci were histologically assessed by H&E and Masson's trichrome stain and treated with KMUP-1 and references. Lung tissues were determined the contents of collagen and the expressions of TGF-β, α-SMA, HMGB1, CTGF, eNOS, p-eNOS, RhoA, Smad3, p-Smad3, MMP-2 and MMP-9 by Western blotting analyses, respectively. These changes areregulated by NO/cGMP and inhibited by various treatments. KMUP-1 and KMUP-1S predominantly prevented HMGB1/MMP-2 expression at day-7 and reduced TGF-β/phosphorylated Smad3 and CTGF at day-28.


KMUP-1 and KMUP-S restore eNOS, inhibit iNOS/ROCKII/MMP-2/MMP-9, attenuate histologic collagen disposition and reduce BALF inflammatory cells, potentially useful for the treatment of BLM-lung PF.

Copyright © 2013 Elsevier Ltd. All rights reserved.


ALT; AST; BAL; Fibrosis; HMGB1; IHC; Inflammation; MMP-2/-9; MMPs; NO; NO/eNOS; PDE-5A; PF; PI; PVDF; Pulmonary; ROCKII; ROS; Rho kinase II; SDS; Smad3; TGF-β1; TGFβ; alanine aminotransferase; aspartate aminotransferase; broncholaveolar lavage fluid; cGMP; eNOS; endothelial nitric oxide synthase; guanosine 3′,5′-cyclic monophosphate; high mobility group box 1; iNOS; immunohistochemistry; inducible NOS; matrix metalloproteinases; matrix metalloproteinases-2 and -9; mouse mothers against decapentaplegic homolog 3; nitric oxide; p-Smad3; p-eNOS; phosphodiesterase 5A; phosphorylated Smad3; phosphorylated eNOS; polyvinylidene; pulmonary fibrosis; pulmonary inflammation; reactive oxygen species; sodium dodecyl sulfate-polyacrylamide gel electrophoresis; transforming growth factor-β1

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