Aging lungs may spark runaway inflammation that makes infections far more dangerous.
University of California - San Francisco
These findings provide new insight into age-related
inflammation and help explain why something as simple as a cough can sometimes
lead to hospitalization in older individuals.
Aging Lung Cells and Inflammation
To explore what changes in older lungs, researchers focused
on fibroblasts, the structural cells that help maintain lung tissue. In
experiments with young mice, they activated a stress signal typically linked to
aging. This caused the lungs to develop clusters of inflamed cells, including
some marked by the GZMK gene, which was first identified in severe COVID-19
cases. Scientists believe future treatments could target these cells to
interrupt the harmful cycle known as inflammaging.
"We were surprised to see lung fibroblasts working
hand-in-hand with immune cells to drive inflammaging," said Tien Peng, MD,
a professor of Medicine and a member of the Cardiovascular Research Institute
and Bakar Aging Research Institute at UCSF. "It suggests new ways to
intervene before patients progress to severe inflammation that can require
intubation."
Peng is the senior author of the study, published in Immunity on
March 27. Nancy Allen MD, PhD, a clinical fellow in the Pulmonary and Critical
Care Division in the UCSF Department of Medicine, is the first author.
Fibroblasts and the NF-kB Pathway
Fibroblasts play a key role in keeping the lungs' airways
and air sacs stable and functional. However, they are also known to contribute
to inflammation in conditions such as COPD. The research team wanted to
determine whether signals from these cells could disrupt otherwise healthy
lungs.
They examined a pathway called NF-kB, which is commonly
associated with aging-related diseases. When activated, fibroblasts signaled
macrophages in the lungs to initiate an immune response. This response then
drew additional immune cells from the bloodstream, including those marked by
GZMK.
Although these GZMK cells were not effective at fighting
infection, they were still able to damage lung tissue.
Immune Cell Clusters and Lung Damage
After these clusters of immune cells formed, the young mice
developed severe symptoms when infected, resembling the response typically seen
in older adults. When researchers used a genetic method to remove the GZMK
cells, the mice were better able to tolerate the infection.
This finding suggests that aging lung tissue itself may be a
major driver of harmful inflammation.
The researchers also examined lung tissue from older
patients hospitalized with COVID-related ARDS (acute respiratory distress
syndrome). These samples contained similar clusters of inflamed cells to those
observed in the mice. Patients with more severe illness had a greater number of
these clusters, while healthy donor lungs showed none.
"We saw during COVID that our most vulnerable patients
no longer had the infection but still had persistent and devastating lung
inflammation," Peng said. "This circuit of dysfunction between lung
and immune cells makes for a promising new therapeutic target."
Journal Reference:
- Nancy
C. Allen, Christian Ringler, Sang Ho Woo, Sophie Phipps, Jin Young Lee,
Nabora Reyes, Ritusree Biswas, Lucile Neyton, Andrew Willmore, Sofia
Caryotakis, Jessica Roginsky, Lu Guo, Melia Magnen, Pedro Ruivo, Chaz
Langelier, Mark Looney, Averil Ma, Vincent Auyeung, Carolyn Calfee, Ari B.
Molofsky, Tien Peng. NF-κB-activated fibroblasts orchestrate
inflammaging and emergence of pro-inflammatory granzyme K T cells. Immunity,
2026; DOI: 10.1016/j.immuni.2026.02.016