Why are older people at higher risk for lung injury, especially after trauma? The answer may lie in the macrophages, the immune cells that live in the air spaces of the lungs.
As a student at the University of Colorado School of Medicine, Devin M. Boe, MD, PhD — now a resident at Georgetown University School of Medicine — conducted research showing that aging impacts macrophages in the lung, causing them to be unable to work as effectively when the body is subjected to trauma. His paper was published in September in the Journal of Leukocyte Biology.
“The elderly are at much higher risk of lung infections and lung disease in general; we know that the immune system of the lungs gets dysregulated with age,” Boe says. “We wanted to know what's going on chronically in healthy aging that affects that — what happens to the cells over time as an organism ages that explains why those cells may not be functional in the elderly.”
Differing levels of response
Using animal models of different ages, Boe and his fellow researchers found that when subjected to a distal injury, the macrophages in young lung cells responded immediately and dramatically to the release of stress hormones called glucocorticoids, allowing them to mount a controlled immune response, while the macrophages in older lung cells had virtually no response to the stress hormones.
“What we found was that there is a particular protein called fkbp5 that is responsible for blocking the response to those stress hormones — it inhibits the glucocorticoid receptor and prevents the stress hormones from signaling within the cell and changing gene expression,” Boe says. “In the cells from young subjects, levels of fkbp5 went through the roof after injury, indicating that those pathways were activated. However, in macrophages from the aged, fkbp5 was already very elevated, suggesting that that protein may be responsible for why the older subjects were not responding to the stress hormones.”
The effects of stress on stress
It will take further research to tell if the elevation of fkbp5 is a natural result of aging in cells or the result of long-term exposure to the stress hormones, Boe says, though in humans the protein is found in higher levels in people who suffer adverse life events or chronic illness. It’s possible, he says, that chronic stress causes cells to become desensitized to acute stress.
“The next step after this is how do we restore that proper response?” he says. “If we can inhibit fkbp5 at the molecular level, if we can restore responsiveness to the stress hormones, then maybe the macrophages can function in their proper role of controlling that inflammation and secondary tissue damage.”
Part of a larger effort
Boe conducted his research in the lab of Elizabeth J. Kovacs, professor of GI, trauma, and endocrine surgery, who has long been interested in the effects of aging on immunity.
“In the context of trauma, it has been documented by our group and others that older folks don't do as well, even with very small burns,” Kovacs says. “They have difficulty responding to an infectious pathogen, which is often the sequelaeafter burn injury, whether that infection is on their skin, in their lungs, or some other compartment.”
Boe’s research, she says, offers one reason why that could be happening, especially in the lungs, where the job of the macrophages is to “eat” bacteria and dangerous molecules. When their ability to do so is impaired by age, the bacteria can proliferate and cause infection.
“One of the purposes of these cells is to act like a sentinel, protecting that tissue from potential injury or infection,” Kovacs says. “Alveolar macrophages are primarily anti-inflammatory, to quiet down any excess inflammation that might happen. But after trauma, they shift their phenotype and become more proinflammatory. And that can be deleterious because they may release hydrolytic enzymes that cause tissue damage.”
