In a new study, UCSF researchers showed that they could successfully redirect profibrotic murine lung cells to a nonfibrotic state in which they regenerated alveoli. These findings could lead to novel treatments for lung injury and fibrosis.
Vincent Auyeung, MD, PhD, was first author on the study and Dean Sheppard, MD, and Feroz Papa, MD, PhD, were senior authors.
“The largest source of acute lung injury in the last few years has been COVID-19, and we believe many patients may present with post-COVID fibrosis,” said Auyeung. “We are trying to understand if we can redirect lung epithelial cells towards a nonfibrotic state.”
Alleviating fibrosis and accelerating lung repair
After lung injury, damage-associated transient progenitors (DATPs) emerge, representing a transitional state between injured epithelial cells and newly regenerated alveoli. DATPs express profibrotic genes, which suggests that they may promote idiopathic pulmonary fibrosis (IPF). The molecular mechanisms that control entry into the transitional state and those that abnormally maintain it are not well understood.
“We’ve recognized the presence of DATPs in fibrotic lung disease and any severe, acute lung injury,” Auyeung said. “In mice, these cells have the capacity to differentiate into new lung alveolar cells. We want to understand how cells in this transitional state decide to proceed with differentiation, and what they sense in the outside environment that would cause them to either continue to differentiate or remain in this transitional state.”
The UCSF researchers found that the IRE1 alpha protein (IRE1α), a bifunctional kinase/RNase, promotes DATP abundance and function. IRE1α is a central mediator of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress. Previous work in Dr. Papa’s lab at UCSF had shown that IRE1α functions as a cellular life-versus-death switch under high and chronic ER stress. The new findings add to the growing understanding of the role of IRE1α-mediated cell fate determination under unchecked ER stress.
For the study, the UCSF researchers used a kinase inhibitor of IRE1α, known as kinase-inhibiting RNase attenuator 8 (KIRA8), to reduce DATP cell numbers in mice with bleomycin-induced lung injury. The researchers concluded that blocking IRE1α signaling helps resolve the DATP phenotype, alleviating fibrosis and accelerating normal lung repair in mice.
Preclinical translational research
Auyeung hopes to conduct preclinical translational studies in the near future. “We’re interested in using human translational lung models to understand whether this pathway is important in fibrotic human lungs,” he said. “This research relies on the exceptional lung transplant program at UCSF.”
UCSF environment uniquely conducive to collaboration
The KIRAs used in the study were developed in Dr. Papa’s lab. His team had previously shown that KIRAs could protect mice from experimental pulmonary fibrosis induced by bleomycin exposure. “Around that time, the team working in (UCSF pulmonologist) Hal Chapman’s lab was characterizing the transitional state cells with progenitor cell capacity,” Auyeung said. “This collaboration highlights one of the great things about doing research at UCSF. I don’t think this work could have happened anywhere else.”
UCSF Medical Center is No. 11 in the nation for pulmonology and lung surgery, according to U.S. News & World Report’s 2021-2022 Best Hospitals survey.
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