Upregulation of activin-B and follistatin in pulmonary fibrosis - a translational study using human biopsies and a specific inhibitor in mouse fibrosis models.

Abstract

BACKGROUND:

Activins are members of the TGF-ß superfamily of growth factors. First, we identified by expression array screening that activin-B and follistatin are upregulated in human idiopathic pulmonary fibrosis (IPF). Next, we wanted to clarify their specific role in lung fibrosis formation.

METHODS:

We used specific antibodies for activin-A and -B subunits and follistatin to measure and localize their levels in idiopathic pulmonary fibrosis and control lung biopsies. To inhibit activin signaling, we used soluble activin type IIB receptor fused to the Fc portion of human IgG1 (sActRIIB-Fc) in two different mouse models of pulmonary fibrosis.

RESULTS:

Activin-B and follistatin mRNA levels were elevated in the human IPF lung. Immunoreactivity to activin-A, -B and follistatin localized predominantly to the hyperplastic, activated alveolar epithelium, but was also seen in inflammatory cells. Mice treated with sActRIIB-Fc showed increased skeletal muscle mass and a clear reduction in alveolar cell counts in bronchoalveolar lavage fluid, but no significant antifibrotic effect in the lung was observed.

CONCLUSIONS:

The upregulation of activin-B and follistatin in IPF is a novel finding. Our results indicate that activin inhibition is not an efficient tool for antifibrotic therapy, but could be useful in reducing alveolar cellular response to injury. Activin-B and follistatin levels may be useful as biomarkers of IPF.

• Authors: Marjukka Myllärniemi, Jussi Tikkanen, Juha J Hulmi, Arja Pasternack, Eva Sutinen, Mikko Rönty, Outi Leppäranta, Hongqiang Ma, Olli Ritvos, Katri Koli
• Journal: BMC pulmonary medicine (BMC Pulm Med) Vol. 14 Pg. 170 (Nov 01 2014) ISSN: 1471-2466 [Electronic] England
• PMID: 25361680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Follistatin
• Inhbb protein, mouse
• RNA, Messenger
• Recombinant Fusion Proteins
• activin B
• inhibin beta A subunit
• sActRIIB-Fc fusion protein
• Activins
• Inhibin-beta Subunits

Topics

• Activins (drug effects, genetics, metabolism)
• Animals
• Bronchoalveolar Lavage Fluid (cytology)
• Cell Count
• Disease Models, Animal
• Follistatin (genetics, metabolism)
• Humans
• Immunity, Cellular (drug effects)
• Inhibin-beta Subunits (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Protein Biosynthesis
• Pulmonary Alveoli (chemistry, immunology)
• Pulmonary Fibrosis (metabolism)
• Quadriceps Muscle (anatomy & histology, drug effects)
• RNA, Messenger (metabolism)
• Recombinant Fusion Proteins (pharmacology)
• Respiratory Mucosa (chemistry, immunology)
• Signal Transduction
• Up-Regulation (drug effects)