Aging and senescence in alveolar epithelial type II cells affect progenitor cell function and aggravate acute lung injury

Abstract

Survival and regeneration in acute lung injury (ALI) decrease with age. Alveolar epithelial type 2 cells (AE2) are crucial for repair as they proliferate and transdifferentiate into alveolar epithelial type 1 cells. We hypothesized that aging and cellular senescence impair AE2 progenitor function and recovery in ALI with aging. To differentiate between the impact of old age and AE2 senescence, we used young (3 months) mice with Trf1-KO (SftpcCre-tdTomato-Trf1−/−) and young and old (18 months) mice without (SftpcCre-tdTomato). Tamoxifen-treatment caused AE2 specific cellular senescence in Trf1-KO mice and red fluorescence in AE2 of all mice. ALI was induced by intranasal application of 1 µg lipopolysaccharide (LPS)/g BW (n=9-11) or saline (controls; n=7). Mice were sacrificed 4 or 7 days later. Lung function testing and assessment of pulmonary inflammation were done, as well as stereological analysis of AE2 number, surface area, proliferation and transdifferentiation rate. All young mice with and without Trf1-KO recovered by day 7, however, only 45 % of the old mice survived day 4. Pulmonary inflammation was most severe in old mice, followed by young Trf1-KO mice. In young mice without Trf1-KO, an expansion of AE2 number and surface area was measured. This was not the case in Trf1-KO mice and to a lesser extend in old mice. Transdifferentiation rate upon LPS challenge did not change with age or AE2 senescence. The results show that transdifferentiation rate was not affected by AE2 senescence or old age, however, the AE2 proliferation was reduced and an increased pulmonary inflammation, particularly in old mice, contributed to an enhanced severity in ALI.