Aging causes alveolar epithelial type II cell dysfunction in acute lung injury

Abstract

Morbidity and mortality rates in acute lung injury (ALI) increase in the elderly. Alveolar epithelial type II cells (AE2) are crucial for lung function and repair, but the impact of AE2 aging on the development of ALI remains unknown. We hypothesized that aging promotes senescence and metabolic alterations in AE2 and thereby contributes to a worse injury and impaired regeneration in ALI. ALI was induced in young (3 months) and old (18 months) mice with 2.5 μg lipopolysaccharide (LPS)/g body weight. Control mice received saline. Lung function was tested 24 h, 72 h and 10 d later. AE2 number, apoptosis, proliferation and ultrastructural changes in lamellar bodies were quantified with stereology. Surfactant activity was assessed with a captive bubble surfactometer. AE2, isolated from control and LPS-treated mice, were analyzed for cell senescence, inflammatory signaling and changes in surfactant metabolism. In old mice, surfactant activity was severely impaired. ALI induced a high mortality rate (60% by day 5) and lung function decline in old, but not in young mice. In young mice, numerical density of AE2 was 26% higher compared to old mice and AE2 of young mice adapted to injury by increasing intracellular surfactant volume and proliferation rate. In old mice, however, this adaptive response was compromised and AE2 of old mice showed signs of cell senescence (p21, p53, γH2AX), increased inflammatory signaling and impaired surfactant metabolism in ALI. Here we show for the first time that AE2 function was reduced in ALI with age. Particularly surfactant metabolism, inflammatory signaling and proliferation rate, that are crucial for lung function and repair after injury, were impaired in AE2 of old mice with ALI and supported the worse pathophysiology of the disease with aging.