Neutrophil Aggregates and Elastin Degradation Compromise Lung
Architecture in Fatal COVID-19
Abstract
Pulmonary fibrosis, profound alveolitis, and the failure to restore
alveolar epithelial architecture are major causes of respiratory failure
in fatal COVID-19. However, contributing factors to abnormal fibrosis in
critically ill COVID-19 patients are yet to be understood. This study
analyzed the histopathology of lung autopsy samples from eight COVID-19
and six non-COVID-19 post-mortems. The distribution and changes in
extracellular matrix (ECM) proteins, including elastin and collagen in
lung alveoli, were quantitatively assessed through morphometric
analyses. These studies reveal massive degradation of elastin fibers
along the thin-alveolar walls of the lung parenchyma that supersedes
interstitial collagenous fibrosis and intra-alveolar fibrotic
abnormalities. Injured lungs with collapsed alveoli and organized
fibrotic regions exhibited widespread elastolysis. Further,
immunoblotting of lung autopsy extracts validated extensive elastin
degradation. Importantly, loss of elastin was correlated with induction
of neutrophil elastase (NE), a potent protease that degrades ECM, and
increased staining of peptidylarginine deiminase, a marker for
neutrophil extracellular traps release, and extensive epithelial
necrosis. Further, elevated plasma levels of NE-alpha1-antitrypsin
complex in hospitalized COVID-19 patients indicate dysregulated
neutrophil activity. These findings place elastin degradation at the
center of alveolar structural disintegration and argue that elastolysis
and alveolitis lead to abnormal ECM repair and fibrosis in fatal
COVID-19.