Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this — done in service to humanity — now hangs in the balance due to the government’s decision to terminate large numbers of federally funded grants and contracts across Harvard University.
When the lungs are attacked by a virus, the damage doesn’t stop there. The body’s natural defenses cause inflammation while fighting the virus, often leaving lasting problems.
Studying mice and lung organoids, a team of Harvard Medical School researchers has now revealed that macrophages — a type of immune cell — may be key to repairing that damage to the lungs’ mucosal lining, both from the initial infection and from the immune response itself.
The team found that macrophages in the mouse lung produce a growth factor, oncostatin M (OSM), that can quickly restore the epithelial cells that line and protect the lung.
Though the work is so far limited to animal models and cell cultures, the results offer a new strategy in efforts to develop regenerative therapies that repair damaged lung tissue. Such therapies would benefit people who successfully fight off severe viral infections only to succumb to ongoing lung inflammation caused by the immune system, as well as those who suffer from inflammation-related chronic lung disease and scarring (fibrosis).
Findings from the study, supported in part by federal funding, are published in Science.
“A lot of the time people who die on ventilators from diseases like COVID-19 or severe viral pneumonia have actually cleared the virus, but they can’t fix their lungs in the context of all of this inflammation,” said co-first author Daisy Hoagland, research fellow in immunology in the lab of Ruth Franklin in the Blavatnik Institute at HMS. “We’re really hopeful that OSM could be therapeutically beneficial in those situations.”
When the lungs become infected, the organ’s first priority is to fight the infection. Doing so may entail the immune system trying to kill the infected cells, Hoagland said.
This inflammatory reaction can have harmful consequences alongside the beneficial ones.
While an infection is raging, it’s hard for the body to repair the lung epithelial barrier because many of the inflammatory signals intended to destroy the virus also prevent cells from replicating — redirecting them toward defense programs instead of regeneration, Hoagland said.
The team found that OSM helped overcome these signals and promote regeneration in mouse models of flu infection.
“Repairing the damage from viral infection and from inflammation is difficult while an infection is ongoing, but OSM can override some of these signals and restore the barrier,” said Franklin, assistant professor of stem cell and regenerative biology at HMS and senior author of the study.
Franklin and team studied mice that had been bioengineered to prevent production of OSM and infected them with the influenza virus.
“By nearly every metric that we checked, mice lacking OSM had more damage than normal mice,” Hoagland said.
The next step involved using a synthetic virus-like molecule, poly(I:C), that doesn’t replicate like a real virus but nonetheless triggers an immune response, activating the same inflammatory signals that usually prevent cells from dividing.
Using poly(I:C) on both the OSM-deficient mice and normal mice led to the same conclusion: OSM is essential to helping the lung’s protective lining heal during the immune system’s antiviral response.
This discovery follows on years of studies of OSM that began around 2014, noted Franklin. In addition to further investigating whether the molecule holds therapeutic promise, she is interested in learning what OSM does when there is no infection.
“What we found is that OSM is produced at low levels in the absence of inflammation,” she said. “We’re currently trying to understand the role of OSM at baseline.”
Adapted from an article in the Harvard Gazette.
Authorship, funding, disclosures
Patricia Rodríguez-Morales, who conducted the work as a Harvard Kenneth C. Griffin Graduate School of Arts and Sciences PhD student in the Franklin Lab, is co-first author. Additional authors are Alexander O. Mann, Alan Y. Baez Vazquez, Shuang Yu, Alicia Lai, Harry Kane, Susanna M. Dang, Yunkang Lin, Louison Thorens, Shahinoor Begum, Martha A. Castro, Scott D. Pope, Jaechul Lim, Shun Li, Xian Zhang, Ming O. Li, Carla F. Kim, Ruaidhrí Jackson, and Ruslan Medzhitov.
This work was supported by the National Institutes of Health (grants R35GM150816, P30DK043351, RC2DK135492, R01AI182061, TL1TR002543, F31HL172650, U01CA267827, R35HL150876, DP2AI169979, R01CA272717, Cancer Center Support grant P30CA08748), Mazumdar-Shaw Translational Research Initiative in Kidney Cancer, Charles H. Hood Foundation, Harvard Stem Cell Institute, Cancer Research Institute Irvington Donald J. Gogel Postdoctoral Fellowship, National Science Foundation Graduate Research Fellowship Program (grant DGE1122492), Blavatnik Family Foundation, Scleroderma Research Foundation, Howard Hughes Medical Institute, and Landry Cancer Biology Research Fellowship.
The authors also acknowledge the Immunology Flow Cytometry Core, Microscopy Resources on the North Quad (MicRoN) Core, Single Cell Core, Biopolymer Facility, Harvard Center for Comparative Medicine, and Rodent Histopathology Core at HMS.
Franklin, Hoagland, Rodríguez-Morales, and Medzhitov are inventors on a provisional patent application submitted by the President and Fellows of Harvard College and Yale University that covers aspects of the work presented here. Kim is the cofounder of Cellforma.
