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Researchers Say They've Found Tiny Extracellular Entity That Causes COPD Damage

AJMC Staff
Researchers said they found a previously unreported pathogenic entity that links chronic inflammation and tissue destruction in the lungs of patients with chronic obstructive pulmonary disease (COPD).
Researchers said they found a previously unreported pathogenic entity that links chronic inflammation and tissue destruction in the lungs of patients with chronic obstructive pulmonary disease (COPD).

Exosomes from activated polymorphonuclear leukocytes, or PMNs, caused COPD damage when the small, subcellular particles, collected from purified PMNs, were infused into the lungs of healthy mice. COPD is marked by PMN-driven inflammation in the lungs. PMN neutrophils defend against infections and tissue damage and consume microbes or damaged human cells after activation by a signal of infection. Exosomes are tiny extracellular membrane-bound vesicles that mediate cell-to-cell communication, and they carry proteins, lipids, and nucleic acids from cell to cell.

"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," said J. Edwin Blalock, PhD, professor of pulmonary, allergy, and critical care medicine in the University of Alabama Department of Medicine, in a statement.

Activated PMNs are known to release neutrophil elastase (NE), a protease that can degrade type 1 collagen and elastin. The collagen and elastin proteins help form the extracellular matrix that glues cells together. In the lungs, the extracellular matrix and lung cells are sheets of tissue that help form the tiny alveoli, where the lung exchanges oxygen and carbon dioxide.

In COPD, the damaged alveoli enlarge, reducing oxygen exchange and forcing the heart to pump harder to push blood through the lungs. NE and other proteases from PMNs can attack microbes. Healthy lungs are protected by antiproteases that can inhibit the proteases. Normally, NE is inhibited by a robust barrier of alpha1-antitrypsin in the lung.

Blalock and fellow researchers investigated whether NE might exist in an exosomal form and whether such exosomes might bypass alpha1-antitrypsin inhibition to contribute to inflammatory lung disease. They found that exosomes from inactive PMNs did not cause COPD when transferred to healthy mice.

However, exosomes from activated PMNs did cause COPD, as measured by histologic changes of the alveoli, increased pulmonary resistance, and enlargement of the right heart ventricle that pumps blood to the lung. In the study, human COPD lung-derived exosomes carrying those PMN cell-surface markers conferred COPD to mice.

The activated PMN exosomes were covered with enzymatically active surface-bound NE, while inactive exosomes had none. This surface NE was resistant to alpha1-antitrypsin inhibition; the exosomes from activated PMNs degraded collagen, they caused emphysema when put into mouse lungs, and they carried the PMN cell-surface markers CD63 and CD66b that identify them as coming from PMNs.

A very large dose of purified NE, enough to overwhelm the alpha1-antitrypsin barrier, can cause alveolar enlargement in mice. Because the exosome-bound NE was protected against apha1-antitrypsin inhibition, researchers found that the dose of activated PMN exosomes needed to cause the same damage as purified NE was 10,000 times less.

Reference

Genschmer KR, Russell DW, Lal C, et al. Activated PMN exosomes: pathogenic entities causing matrix destruction and disease in the lung [published online January 10, 2019]. Cell. doi: 10.1016/j.cell.2018.12.002.

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