Michigan Postdoctoral Pioneer Program, 2021

Collaborative PIs


Daniel R. Goldstein, M.D.

Eliza Maria Mosher Collegiate Professor of Internal Medicine
Editor-in-Chief, Journal of Heart and Lung Transplantation, https://www.jhltonline.org/
University of Michigan, Ann Arbor USA


Co - Mentor

Jane Deng, M.D., M.S.

Head of Pulmonary VA Medical Center Ann Arbor
Associate Professor of Medicine
University of Michigan, Ann Arbor USA




Role of aging in the inflammation to acute respiratory viral infections  

Older people exhibit high morbidity and mortality after respiratory viral lung infection. Regrettably, options for prevention and treatment of respiratory viruses including influenza and SARS-CoV-2 in older individuals are limited, and vaccination is less effective in older people than in younger people. Reducing the impact of respiratory viral infection in older people in particular requires novel therapies that can effectively reduce mortality with aging. Respiratory viral infections 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 respiratory 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 (Adjacent Figure). As alveolar macrophages are key in clearing debris and resolving inflammation, we postulate that impairments in alveolar macrophages with aging inhibit inflammation resolution during viral infection. In Aim 1, we will examine the mechanisms by which senescent alveolar epithelial cells enhance neutrophil recruitment and retention into the lung during respiratory 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 respiratory 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.

Overall Hypothesis. Age-enhanced mortality during influenza infection is due to altered interactions between AMs and AECs. Senescent AECs from aged hosts secrete more neutrophil chemokines (CXCL1/2) and PGE2 upon influenza infection, pathologically enhancing neutrophil recruitment to the lung. PGE2 signals to AMs to reduce the AM population size and to reduce efferocytosis. Combined, the impact of aging is to increase PMNs during influenza infection promoting mortality.