MS80, a novel sulfated oligosaccharide, inhibits pulmonary fibrosis by targeting TGF-beta1 both in vitro and in vivo.
OBJECTIVE
The pro-fibrogenic cytokine transforming growth factor-beta 1 (TGF-beta1) has attracted much attention for its potential role in the etiology of idiopathic pulmonary fibrosis (IPF). Here, we demonstrate that MS80, a novel sulfated oligosaccharide extracted from seaweed, can bind TGF-beta1. The aim of the present study was to determine whether MS80 is capable of combating TGF-beta1-mediated pulmonary fibrotic events both in vitro and in vivo, and to investigate the possible underlying mechanisms.


METHODS
Surface plasmon resonance was used to uncover the binding profiles between the compound and TGF-beta. MTT assay, flow cytometry, Western blot analysis, BCA protein assay and SDS-PAGE gelatin zymography were used to probe the antifibrotic mechanisms of MS80. The in vivo fibrotic efficacy was evaluated in a bleomycin instillation-induced rat model.


RESULTS
We report that MS80, a new kind of sulfated oligosaccharide extracted from seaweed, inhibits TGF-beta1-induced pulmonary fibrosis in vitro and bleomycin-induced pulmonary fibrosis in vivo. Our results indicated that MS80 competitively inhibited heparin/HS-TGF-beta1 interaction through its high binding affinity for TGF-beta1. Moreover, MS80 arrested TGF-beta1-induced human embryo pulmonary fibroblast (HEPF) cell proliferation, collagen deposition and matrix metalloproteinase (MMP) activity. Intriguingly, MS80 deactivated both the ERK and p38 signaling pathways. MS80 was also a potent suppressor of bleomycin-induced rat pulmonary fibrosis in vivo, as evidenced by improved pathological settings and decreased lung collagen contents.


CONCLUSIONS
MS80 in particular, and perhaps oligosaccharide in general, offer better pharmacological profiles with appreciably few side effects and represent a promising class of drug candidates for IPF therapy.Acta Pharmacologica Sinica (2009) 30: 973-979; doi: 10.1038/aps.2009.86; published online 22 June 2009.
Jiang
Han-Dong
HD
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Guan
Hua-Shi
HS
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry / Q000627:therapeutic use*; D011485:Protein Binding; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012624:Seaweed / Q000737:chemistry; D015398:Signal Transduction / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C545090:MS80 oligosaccharide; D009844:Oligosaccharides; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases