Science and Research

Senescence in Alveolar Epithelial Type II Cells Promotes Acute Lung Injury and Impairs Regeneration

Mortality of acute lung injury (ALI) increases with age. Alveolar epithelial type 2 cells (AEII) are the progenitor cells of the alveolar epithelium and crucial for repair after injury. We hypothesize that telomere dysfunction-mediated AEII senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII senescence in ALI, young (3 months) and old (18 months) Sftpc-Ai9 mice and young Sftpc-Ai9-Trf1 mice with inducible Trf1 knockout-mediated senescence in AEII were treated with 1 µg lipopolysaccharide (LPS)/g BW (n=9-11). Control mice received saline (n=7). Mice were sacrificed 4 or 7 days later. Lung mechanics, pulmonary inflammation and proteomes were analyzed and parenchymal injury, AEII proliferation and AEI differentiation rate were quantified using stereology. Old mice showed 55% mortality by day 4, whereas all young mice survived. Pulmonary inflammation was most severe in old mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by day 7, while Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII was only measured in young Sftpc-Ai9 mice at day 7. Aging and telomere dysfunction-mediated senescence had no impact on AEI differentiation rate in controls, but the reduced number of AEII in Sftpc-Ai9-Trf1 mice also affected de-novo differentiation after injury. In conclusion, telomere dysfunction-mediated AEII senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. While Differentiation rate remained functional with old age and AEII senescence, AEII proliferative capacity was impaired in ALI, affecting the regenerative ability.

  • Hirsch, M. S.
  • Hildebrand, C. B.
  • Geltinger, F.
  • Pich, A.
  • Mühlfeld, C.
  • Wedekind, D.
  • Brandenberger, C.

Keywords

  • acute lung injury
  • alveolar epithelial type II cells
  • cellular senescence
  • pulmonary aging
  • telomere dysfunction
Publication details
DOI: 10.1165/rcmb.2024-0054OC
Journal: Am J Respir Cell Mol Biol
Work Type: Original
Location: Assoziierter Partner, BREATH
Disease Area: PALI
Partner / Member: BIH, MHH
Access-Number: 39088755

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