Journal Article

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

Brandenberger, Christina, Hirsch, Merle S., Pich, Andreas, Hildebrand, Christina B., Geltinger, Florian, Mühlfeld, Christian, Wedekind, Dirk

2024

Overview

The mortality associated with acute lung injury (ALI) increases with age. Alveolar epithelial type II (AEII) cells are the progenitor cells of the alveolar epithelium and are crucial for repair after injury. We hypothesize that telomere dysfunction–mediated AEII cell senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII cell senescence in ALI, young (3 mo) and old (18 mo) Sftpc-Ai9 mice with surfactant protein c mediated tdTomato expression, and young Sftpc-Ai9-Trf1 mice with additional telomeric repeat-binding factor 1 (Trf1) knockout–mediated senescence in AEII cells were treated with 1 μg LPS per gram body weight (n = 9–11). Control mice received saline solution (n = 7). Mice were killed 4 or 7 days later. Lung mechanics, pulmonary inflammation, and proteomes were analyzed, and parenchymal injury, AEII cell proliferation and AEI cell 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 Sftpc-Ai9 mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by Day 7, whereas Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII cells was measured only 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 cells in Sftpc-Ai9-Trf1 mice also affected de novo differentiation after injury. In conclusion, telomere dysfunction– mediated AEII cell senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. Although the differentiation rate remained functional with old age and AEII cell senescence, AEII cell proliferative capacity was impaired in ALI, affecting the regenerative ability.

• Publisher: Oxford University Press
• Subject: Acute Lung Injury - metabolism / Acute Lung Injury - pathology / Aging / Aging - metabolism / Aging - pathology / Alveolar Epithelial Cells - metabolism / Alveolar Epithelial Cells - pathology / Alveoli / Animals / Cell Differentiation / Cell Proliferation / Cells / Cellular Senescence / Geriatrics / Inflammation / Lung diseases / Lungs / Mice / Mice, Inbred C57BL / Older people / Pulmonary Surfactant-Associated Protein C - genetics / Pulmonary Surfactant-Associated Protein C - metabolism / Regeneration / Senescence / Telomere - metabolism / Telomeres / Transgenic mice