Growth Differentiation Factor 11 Evokes Lung Injury, Inflammation, and Fibrosis in Mice through the Activin A Receptor Type II-Like Kinase, 53kDa-Smad2/3 Signaling Pathway.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0370502 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-2191 (Electronic) Linking ISSN: 00029440 NLM ISO Abbreviation: Am J Pathol Subsets: MEDLINE
    • Publication Information:
      Publication: 2011-: New York : Elsevier
      Original Publication: Philadelphia [etc.] American Assn. of Pathologists [etc.]
    • Subject Terms:
      Growth Differentiation Factors*/metabolism ; Signal Transduction* ; Lung Injury*/metabolism ; Lung Injury*/pathology ; Lung Injury*/chemically induced ; Pulmonary Fibrosis*/pathology ; Pulmonary Fibrosis*/metabolism ; Pulmonary Fibrosis*/chemically induced ; Smad2 Protein*/metabolism ; Bone Morphogenetic Proteins*/metabolism ; Smad3 Protein*/metabolism; Animals ; Mice ; Humans ; Male ; Inflammation/pathology ; Inflammation/metabolism ; Mice, Inbred C57BL ; Activin Receptors, Type II/metabolism
    • Abstract:
      Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor beta superfamily and participates in various pathophysiological processes. Initially, GDF11 was suggested to act as a rejuvenator by improving age-related phenotypes of the heart, brain, and skeletal muscle in aged mice. Recent studies demonstrate that GDF11 also serves as an adverse risk factor for human frailty and diseases. However, the role of GDF11 in pulmonary fibrosis (PF) remains unclear. This study explored the role and signaling mechanisms of GDF11 in PF. GDF11 expression was markedly up-regulated in fibrotic lung tissues of both humans and mice. Intratracheal administration of commercial recombinant GDF11 caused lung injury, inflammation, and fibrogenesis in mice. Furthermore, adenovirus-mediated secretory expression of mature GDF11 was exacerbated, whereas full-length GDF11 or the GDF11 propeptide (GDF11 1-298 ) alleviated bleomycin-induced PF in mice. In in vitro experiments, GDF11 suppressed the growth of alveolar and bronchial epithelial cells (A549 and BEAS-2B) and human pulmonary microvascular endothelial cells, promoted fibroblast activation, and induced epithelial/endothelial-mesenchymal transition. These effects corresponded to the phosphorylation of Smad2/3, and blocking activin A receptor type II-like kinase, 53kDa (ALK5)-Smad2/3 signaling abolished the in vivo and in vitro effects of GDF11. In conclusion, these findings provide evidence that GDF11 acts as a potent injurious, proinflammatory, and profibrotic factor in the lungs via the ALK5-Smad2/3 pathway.
      Competing Interests: Disclosure Statement None declared.
      (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
    • Accession Number:
      0 (Growth Differentiation Factors)
      0 (Gdf11 protein, mouse)
      0 (Smad2 Protein)
      0 (Bone Morphogenetic Proteins)
      0 (Smad3 Protein)
      EC 2.7.11.30 (Activin Receptors, Type II)
      0 (GDF11 protein, human)
      0 (Smad2 protein, mouse)
      0 (Smad3 protein, mouse)
      EC 2.7.11.30 (Acvrl1 protein, mouse)
    • Publication Date:
      Date Created: 20240815 Date Completed: 20241026 Latest Revision: 20241104
    • Publication Date:
      20241104
    • Accession Number:
      10.1016/j.ajpath.2024.07.016
    • Accession Number:
      39147236