Exosomes — tiny vesicles used for cell communication, released from specific activated immune cells called polymorphonuclear leukocytes — can induce chronic obstructive pulmonary disease (COPD) when transferred to the lungs of healthy mice, a study by researchers at the University of Alabama at Birmingham (UAB) shows.
The study, “Activated PMN exosomes: Pathogenic entities causing matrix destruction and disease in the lung” was published in the journal Cell.
Polymorphonuclear leukocytes, or PMNs, are a special family of white blood cells. They include immune cells known as neutrophils, eosinophils, and basophils. These cells play vital roles in the body’s defense against infections and tissue damage.
Enzymes that break proteins, called proteases, released from PMNs play an important role in some chronic inflammatory diseases in the lung, including COPD.
Neutrophil elastase, or NE, is a PMN-derived protease capable of degrading type I collagen and elastin, two proteins that are part of the extracellular matrix (which provides structural and biochemical support to cells). Release of NE into the airways may cause damage to the lungs.
Healthy lung cells are protected from the damaging effects of proteases by the action of anti-proteases. NE’s anti-protease inhibitor is called alpha1-antitrypsin.
Reduced activity of alpha1-antitrypsin is implicated in COPD, and a genetic deficiency of the enzyme is linked with a spontaneous form of COPD, one that arises even in the absence of exposure to tobacco smoke or other risk factors associated with the disease.
But despite these protective responses, NE is still able to induce lung damage. The question is how.
Researchers at UAB looked at whether NE exists in exosomes, which are known to carry messages encoded as RNA, DNA, or proteins.
The team found that exosomes from activated PMNs, compared to control (non-activated) PMNs, had considerably higher quantities of NE protein.
While control exosomes transferred into healthy mice had no severe impact, exosomes from activated PMNs caused COPD, as shown by changes in the lungs and hearts of the mice.
Researchers also found that the NE proteins at the surface of activated exosomes were resistant to alpha1-antitrypsin inhibition, and capable of degrading collagen and triggering symptoms when injected into the mouse lungs.
Activated exosomes could be distinguished from non-activated ones by specific cell-surface markers, namely two proteins called CD63 and CD66b.
Researchers then isolated human COPD lung-derived exosomes carrying those cell-surface markers, and saw that they triggered COPD when put into healthy mice.
To test whether this mechanism was unique to COPD or was also present in other inflammatory lung diseases, researchers isolated exosomes from lung fluids of intubated babies with a severe lung disease called bronchopulmonary dysplasia. When instilled into the lungs of healthy mice, these human-derived exosomes also caused COPD lung damage. These exosomes were also positive for CD66b.
“This report seems to provide the first evidence of the capability of a defined non-infectious subcellular entity to recapitulate disease phenotype when transferred from human to mouse,” J. Edwin Blalock, PhD, professor of pulmonary, allergy and critical care medicine, department of medicine at UAB, and the study’s lead author, said in a press release. “I think this could be a very profound discovery. A lot of what we have found here will apply in other tissues, depending on the disease.”
NE alone, as a protein, can cause damage to alveoli in mice, but only in very large doses. Because NE at the surface of exosomes was protected against its inhibitor apha1-antitrypsin, researchers saw that exosome-bound NE induced the same damage but at much lower doses (10,000 times lower).
Profiling the activatedexosomes, researchers found that the vesicles carried integrin Mac-1 on their surface, which allowed them to bind directly to collagen fibrils and degrade them.
“Our report significantly expands the biological repertoire of the exosome, demonstrating potent biological effects of these particles ex cellula,” Blalock said.
“These findings highlight a novel role of the innate immune response in chronic lung diseases and could be used for the development of new diagnostics and therapeutics for COPD,” said James Kiley, PhD, director of the division of Lung Diseases at the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.
The team is also looking forward to researching whether PMN-activated exosomes exist in healthy smokers.
“Only one in seven or one in eight smokers gets COPD,” Blalock said. “It would be an amazing outcome if we found activated PMN exosomes in a subpopulation of people who smoke.”
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