Introduction.
The COVID-19 pandemic demonstrated the potentially devastating outcomes
of respiratory viral infections. Although most infected individuals
recover with relatively mild symptoms, many experience impaired lung
function, require hospitalization, and as many as 2% of the infected
patients succumb to the disease caused by the coronavirus CoV-2. To gain
greater insight into the course of fatal COVID-19, lung autopsies from
COVID-19 patients have been examined by histopathology. The disease
reveals a complexity of pathologic features, including acute diffuse
alveolar damage (DAD) and organized pneumonia and
fibrosis.1-6 Growing evidence indicates that during
disease progression, fibrotic abnormalities become more predominant,
especially in fatal COVID-19.7-10 Similarly,
post-acute phase sequelae of COVID-19 chest computed tomography (CT)
scans find a variable degree of fibrotic abnormalities in a large number
of recovered patients.11 In fact, pathologic lesions
caused by fibrosis were also noted earlier in fatal avian influenza,
2003-SARS-COV, and Middle East respiratory syndrome coronavirus
infections.12-15 However, etiologic factors that drive
virus-inflicted pulmonary fibrosis are yet largely unexplored.
Pulmonary fibrosis develops in a complex interplay between cell death,
inflammation, and abnormal ECM remodeling that lead to alveolar
architectural disorganization, irreversible lung dysfunction, and
death.16 Recent studies associate alveolar type II
pneumocyte (AT-II) epithelial injury and endoplasmic reticulum
(ER)-stress-induced impairment of AT-II cell regeneration with
SARS-CoV-2-inflicted fibrotic abnormalities and reveal common features
with idiopathic pulmonary fibrosis (IPF).17 Persistent
neutrophil accumulation and release of neutrophil extracellular traps
(NETs) in the lower respiratory tracts and plasma samples of severely
ill COVID-19 patients and associated with acute alveolar
injury.18-21 Therefore, factors that drive the
disorganization of ECM proteins and abnormal ECM remodeling toward
fibrotic changes in acute SARS-COV-2 infection deserve greater
attention.
Elastin and collagen are major structural ECM proteins in the
alveoli.22 Elastin fibers consist of tropoelastin
polymers, which are cross-linked by lysyl oxidase-mediated conversion of
4 lysine side chains into desmosine.23-24 Elastin
fibers align along the walls of the alveoli by association with
fibrillin-1 and facilitate the expansion and recoiling of alveoli during
normal breathing.25 Unlike other ECM proteins, elastin
has a half-life of 70-80 years, as synthesis of elastin fibers occurs
during the postnatal lung alveolarization and continues during the first
10 years of life in humans.26 The
regeneration/replacement of damaged elastin is inefficient, thus damaged
elastin is often replaced by collagen.27-28 Elastin is
a potent substrate for neutrophil elastase (NE), a serine proteinase
produced by activated neutrophils.29 NE-mediated
elastolysis releases elastin degradative products (EDP), potent
mediators of inflammation and interstitial fibrosis.30Cleavage of elastin is linked to the pathophysiology in
bleomycin-induced fibrosis,31 IPF,32and chronic obstructive pulmonary disease (COPD).33The activity of NE is regulated by an inhibitor called alpha-1
anti-antitrypsin (A1AT), which complexes with NE and blocks its
activity.34-35
In this study, eight lung autopsy samples from COVID-19 patients and six
non-COVID-19 lungs were compared microscopically. Micro-architecture
with progressive elastin cleavage and collagen deposition in injured
lungs correlated with lung pathophysiology, inflammation, and fibrosis.
These observations reveal extensive degradation of elastin fibers in the
alveolar interstitium that shows severe epithelial damage and massive
neutrophil-specific inflammation. Further, loss of elastin and increased
collagen deposits marked lesions with interstitial collagenous fibrosis
and organized parenchymal fibrosis. Elastin degradation was also
observed in areas of alveolar collapse indicating that elastolysis and
alveolitis contribute to abnormal ECM repair and fibrosis in fatal
COVID-19 patients. As proxy for elastase, NE-A1AT complexes in plasma of
a second group of hospitalized COVID-19 patients were quantitated.
Plasma samples from hospitalized patients had approximately 30-fold
higher NE-A1AT complexes than plasmas from healthy donors, suggesting
that such complexes may provide an early warning of host tissue damage
due to inflammation in respiratory lung infections.