Your body fought off the pathogen — but harmed your lungs

When the lungs are assaulted by a pathogen, the injury doesn’t cease there. The body’s inherent defenses induce inflammation while combating the virus, frequently resulting in enduring issues. The cells constituting the lungs’ mucosal lining are exposed to the environment with every inhale — both highlighting the infection risk and underlining the necessity for a strong response. In a recent article published in Science, a group of Harvard researchers discloses how macrophages — a form of immune cell — may be crucial to mend that injury, stemming from both the initial infection and the immune response itself.

“Almost every tissue in the body houses resident macrophages,” clarified Ruth Franklin, assistant professor of stem cell and regenerative biology, whose laboratory conducted the study. These versatile cells “assist in preserving tissue function.”

Issues manifest when the lungs, which routinely encounter pathogens and bacteria, become infected. The primary objective of the organ is to combat the infection. Nevertheless, the body’s response can damage the epithelial cells which line organs and establish their protective barriers.

“Our findings indicate that macrophages in the lung produce a growth factor, oncostatin M (or OSM), capable of rapidly restoring the epithelial barrier in the lung,” Franklin remarked. “This swift repair is incredibly crucial because in the lung, you’re more susceptible to external environments without that barrier.”

Daisy Hoagland, a postdoctoral researcher in Franklin’s laboratory and co-first author of the article, elaborated: “There exist different types of viruses, yet some invade a cell, commandeer all of its machinery, and lead to the cell’s rupture. Additionally, the virus may induce the cell to self-destruct deliberately.

“Much of the devastation occurs because the immune system targets the infected cells,” she continued. “Repairing the epithelial barrier during inflammation is challenging since numerous inflammatory signals hinder cellular replication and redirect cells towards defense mechanisms rather than regeneration.”

To determine whether OSM was vital for the repair of the epithelial barrier, the team examined mice that had been genetically modified to inhibit OSM production and infected them with the influenza virus. “By nearly every metric we assessed, mice deficient in OSM experienced more damage than their normal counterparts,” Hoagland stated.

The subsequent step consisted of utilizing a synthetic virus-like molecule, poly(I:C), which doesn’t replicate like an actual virus but nonetheless incites an immune reaction. Importantly, it activates the same inflammatory signals that usually inhibit cell division. Applying this on both OSM-deficient mice and normal mice yielded similar results. The conclusion? OSM is crucial for facilitating the healing of the lung’s protective lining during the immune system’s antiviral response.

“Cells perish in reaction to both viral infection and the resulting inflammation,” stated Franklin. “Mending this damage is arduous while an infection is active, but OSM can mitigate some of these signals and restore the barrier.”

This recent revelation follows years of research on OSM that commenced around 2014, according to Franklin — “before I arrived at Harvard.” It also paves new avenues for investigation. For instance, Hoagland mentioned that researchers are still uncertain what OSM does in the absence of infection.

“Our findings indicate that OSM is produced at low levels when there is no inflammation,” she noted. “We’re actively working to comprehend the role of OSM at baseline.”

In the meantime, the research team continues their work.

“At present, we’re investigating any therapeutic possibilities for OSM,” Hoagland stated. Although experiments persist in mice, the objective is to determine if OSM could aid in repairing human lungs damaged by disease.

“Often, individuals who pass on ventilators due to ailments like COVID-19 or severe viral pneumonia have in fact eliminated the virus, but they cannot mend their lungs due to the rampant inflammation,” Hoagland remarked. “We are indeed hopeful that OSM could potentially provide therapeutic advantages in such scenarios.”

This research was partially funded by the National Institutes of Health and the National Science Foundation.