Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair.

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  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Alveolar Epithelial Cells*/metabolism ; Diabetes Mellitus, Type 2*/metabolism; Animals ; Mice ; Dipeptidyl Peptidase 4/metabolism ; Lung/metabolism ; Disease Models, Animal
    • Abstract:
      Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to lower airway repair. Agents that promote the selective expansion of these cells might stimulate regeneration of the compromised alveolar epithelium, an etiology-defining event in several pulmonary diseases. From a high-content imaging screen of the drug repurposing library ReFRAME, we identified that dipeptidyl peptidase 4 (DPP4) inhibitors, widely used type 2 diabetes medications, selectively expand AEC2s and are broadly efficacious in several mouse models of lung damage. Mechanism of action studies revealed that the protease DPP4, in addition to processing incretin hormones, degrades IGF-1 and IL-6, essential regulators of AEC2 expansion whose levels are increased in the luminal compartment of the lung in response to drug treatment. To selectively target DPP4 in the lung with sufficient drug exposure, we developed NZ-97, a locally delivered, lung persistent DPP4 inhibitor that broadly promotes efficacy in mouse lung damage models with minimal peripheral exposure and good tolerability. This work reveals DPP4 as a central regulator of AEC2 expansion and affords a promising therapeutic approach to broadly stimulate regenerative repair in pulmonary disease.
      Competing Interests: Competing interests statement:The authors declare no competing interest.
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    • Contributed Indexing:
      Keywords: DPP4; IPF; alveolar stem cells; lower airway repair; regenerative medicine
    • Accession Number:
      EC 3.4.14.5 (Dipeptidyl Peptidase 4)
    • Publication Date:
      Date Created: 20240410 Date Completed: 20240412 Latest Revision: 20240423
    • Publication Date:
      20240423
    • Accession Number:
      PMC11032444
    • Accession Number:
      10.1073/pnas.2400077121
    • Accession Number:
      38598345