The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis

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Abstract

Abstract: In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts’ differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. Highlights: S100A8/A9 level is highly upregulated in the IPF patients’ lungs as well as the blood.S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts.The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts.The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. Graphical abstract: [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)131-145
Number of pages15
JournalJournal of Molecular Medicine
Volume99
Issue number1
DOIs
Publication statusPublished - Jan 2021

Keywords

  • RAGE
  • S100A8/A9
  • biologics
  • fibrosis
  • inflammation
  • lung

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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