Older people exhibit high morbidity and mortality after influenza viral lung infection. Regrettably, options for prevention and treatment of influenza in older individuals are limited, and the influenza vaccine is less effective in older people than in younger people. Reducing the impact of influenza infection in the elderly in particular requires novel therapies that can effectively reduce mortality with aging. Influenza infection causes substantial inflammation, which must be resolved for the lungs to return to normal homeostasis. Unfortunately, little is known about how aging plays a role in inflammation resolution. Our preliminary data in mice provide evidence that acute inflammation, manifested as increased lung damage and neutrophil accumulation within the lungs, persists with aging and suggest that aging dysregulates inflammation resolution. We hypothesize that during influenza viral infection with aging, senescent alveolar epithelial cells secrete neutrophil-attracting chemokines to induce neutrophil recruitment into the lung as well as PGE2, a pleiotropic lipid mediator, which suppresses alveolar macrophage proliferation and function. As alveolar macrophages are key in clearing debris and resolving inflammation, we postulate that impairments in alveolar macrophages with aging inhibit inflammation resolution during influenza infection.
In Aim 1, we will examine the mechanisms by which senescent alveolar epithelial cells enhance neutrophil recruitment and retention into the lung during influenza viral infection with aging.
In Aim 2, we will investigate the mechanisms by which age-related increases in PGE2 impair alveolar macrophages population size and function. Importantly, we will also assess key findings of alveolar epithelial cell senescence, increased neutrophil chemoattractants, increased PGE2 levels, and decreased alveolar macrophage number and function in young and aged human lungs. This work has the potential to elucidate how aging induces an aberrant interaction between alveolar epithelial cells and alveolar macrophages, thereby increasing mortality after influenza viral lung infection. This study could ultimately lead to novel therapies to restore this aberrant interaction induced by aging, resulting in improved survival in older people infected with influenza virus and potentially other respiratory viral pathogens as well.
The elderly exhibit increased morbidity and mortality during influenza viral infections. Our proposal will examine whether the mechanism behind the increased mortality to viral infection with aging is due to dysregulated inflammation resolution. Specifically, we will determine if abnormal interactions between lung epithelial cells and alveolar macrophages lead to dysregulated inflammation and the subsequent increased mortality seen with influenza infection with aging.
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