Investigators studying lung cells have discovered that the normal repair process that occurs after lung disease or injury appears to be incomplete but still ongoing in patients who died of COVID-19 and non-COVID acute respiratory distress syndrome (ARDS).
In patients who survive but develop scarring in the lungs, it appears that the repair process is permanently arrested, leading to chronic fibrotic lung disease. These findings may lead to novel therapies to promote healthy regeneration to increase survival and prevent fibrosis, they report in The American Journal of Pathology.
“We wanted to understand whether incomplete or impaired repair of the damaged lung might contribute to the high mortality rates from COVID-19 and non-COVID ARDS,” explained lead investigator Rachel L. Zemans, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Program in Cellular and Molecular Biology, School of Medicine, University of Michigan, Ann Arbor, MI, U.S. “We also wanted to understand why some survivors of ARDS from COVID-19 have normal lungs but others have scarring that leads to lifelong symptoms.”
The alveolar epithelium in the lungs is made up of two types of cells. Type 1 alveolar epithelial cells (AEC1) are flat and broad and cover most of the alveolar surface. They play a critical role in barrier integrity and facilitate efficient oxygen absorption. Type 2 alveolar endothelial cells (AEC2) are small cuboidal cells that cover the rest of the surface.
They produce a pulmonary surfactant to inflate the lungs and remove fluid. AEC1 and AEC2 are damaged in ARDS due to COVID-19 or other causes. It is known that during lung injury in mice, AEC2 proliferate, exit the cell cycle, and enter a transitional state before changing into AEC1 to repair the alveolar epithelium.
In humans with idiopathic pulmonary fibrosis (IPF), AEC2 never leave the transitional state, and change into AEC1, leading to the development of scar tissue known as fibrosis. The state of epithelial injury and regeneration in COVID-19 and non-COVID-19 ARDS without fibrosis had not been well characterized.
The investigators recovered lung tissue from the autopsies of patients who died of COVID-19 or non-COVID-19 ARDS within two weeks of hospitalization. They were compared with patients with IPF.
The tissue was examined for evidence of AEC2 proliferation, transitional cells, AEC1 differentiation, indications of the loss of the ability to divide (senescence), and fibrosis.
Investigators also compared the gene expression profiles of transitional cells in two mouse models of physiological regeneration without fibrosis, early human COVID-19 and non-COVID-19 ARDS, and human IPF.
The early ARDS lungs had extensive epithelial damage and a regenerative response in which ACE2 proliferated and entered the transitional state. The transitional cells occasionally assumed a flat AEC1 morphology but rarely expressed AEC1 markers. In contrast to patients with IPF, these lungs had not yet developed fibrosis.
“It appears that the stem cells that repair the lungs are able to begin the repair process and assume a ‘transitional’ or intermediate state,” said Dr. Zemans. “However, they have not completely regenerated the cells that were damaged during the injury, leading to acute respiratory failure.”
However, in survivors who develop scarred lungs, AEC1 are never regenerated; cells are stuck in the transitional state which can lead to scarring and lifelong respiratory impairment.
In an accompanying commentary, Thomas R. Martin, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, U.S., observed, “The COVID-19 pandemic has focused attention on severe lung injury, and this new work uses COVID-19 cases to generate a new perspective on lung injury and repair in ARDS.
The results could provide clues about new therapeutic approaches to promote normal repair and/or prevent fibrosis. The results also could be useful in evaluating whether currently available therapies for chronic fibrosis might be helpful early after the onset of acute lung injury.”
The study’s first author Christopher Ting, MD, Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, added, “As a pulmonary and critical care fellow training during COVID-19, I have seen the pandemic highlight a disease process that we have made frustratingly slow progress on. I hope that pursuing the questions our work poses will continue to shed light on how the lung may heal or not heal after injury.”
Post-ARDS lung fibrosis
Radiologically, most patients infected by SARS-COV-2 present with bilateral ground glass opacities with or without consolidation, and with preference of lower lobes (2). However, it should be considered that long-term lung impairment may develop following virus clearance, and in particular fibrotic interstitial lung disease.
Pulmonary fibrosis can be idiopathic and considered as a genetically predisposed, age-related fibroproliferative disease, but chronic inflammation may also be involved in the pathogenesis of lung fibrosis. Importantly, pulmonary fibrosis is a recognised sequelae of ARDS, and several studies have shown that protective lung ventilation tends to diminish the radiographic abnormalities following ARDS (3).
The pathological correlate of ARDS is the diffuse alveolar damage (DAD) which is characterized by an initial (acute inflammatory) exudative phase with edema, hyaline membranes, and interstitial acute inflammation, followed by an organizing phase with loose organizing fibrosis mostly within the alveolar septa, and type II pneumocyte hyperplasia (4).
A potent third and final stage of ARDS may be the fibrotic phase. Thille and coworkers described in a cohort of 159 autopsies from patients with ARDS, stating that these pathological findings can either resolve to normal lung parenchyma or progress to fibrosis (5). In this study, 4% of patients with a disease duration of less than 1 week, 24% of patients with a disease duration of between weeks 1 and 3, and 61% of patients with a disease duration of greater than 3 weeks, developed fibrosis (5). This description along with further data, support that pulmonary fibrosis begins early in the course of ARDS (3).
Abnormal immune mechanisms initiate and promote pulmonary fibrosis, possibly as a consequence of a cytokine storm. Dysregulated release of matrix metalloproteinases during the inflammatory phase of ARDS causes epithelial and endothelial injury.
VEGF and cytokines such as IL-6 and TNFα are also implicated in the fibrotic process. It remains unclear why certain individuals are able to recover from such an insult, whereas others develop accumulation of fibroblasts and myofibroblasts and excessive deposition of collagen resulting in progressive pulmonary fibrosis (6).
The crucial role of macrophages/monocytes, that can exert a proinflammatory or an anti-inflammatory effect based on the microenvironment in different stages, is also well established (7).
Available data indicate that about 40% of patients with COVID-19 develop ARDS, and 20% of ARDS cases are severe (8). The prevalence of post-COVID-19 fibrosis will become apparent in time, but early analysis from patients with COVID-19 on hospital discharge suggests that more than a third of recovered patients develop fibrotic abnormalities.
Additionally, 47% of patients had impaired Diffusing Capacity of the lungs for carbon monoxide (DLCO) and 25% had reduced total lung capacity (TLC). This seemed even worse in patients with severe disease (9). Long-term follow-up is definitely required to determine whether the reticulation represents irreversible fibrosis (10), although it seems that older patients with severe illness during treatment are more prone to develop fibrosis (11). Furthermore, the impact of COVID-19 in the progression of patients with preexisting interstitial lung disease still remains unknown and needs to be studied.
The two other strains of the coronavirus family that have been considered in previous years as highly pathogenic, SARS-CoV and MERS-CoV, are genetically similar to SARS-CoV-2 and cause contiguous lung disease. Data according to previous studies claim that there are reticular changes approximately two weeks after symptom onset in SARS-CoV that persist in half of the patients after one month (12).
Longer follow-up data, 15 years later, showed that there were interstitial abnormalities in 4.6% of patients who had been infected with SARS-CoV (13). Although patients recovered from MERS are less well described in the literature, there is evidence of fibrotic abnormalities in about a third of patients in chest X-rays taken after hospital discharge (14).
Importantly, it has been shown that progressive pulmonary fibrosis can be a cause of mortality in a substantial proportion of patients with ARDS (15), while a considerable proportion of survivors will experience long-term impairment of lung function and radiographic abnormalities suggestive of pulmonary fibrosis (16,17). The extent of reticulation on computed tomography correlates with quality of life and pulmonary function measures that indicate a restriction pattern, such as forced vital capacity (FVC) and DLCO (18).
Taking into consideration these data, even a relatively small degree of residual fibrosis could result in considerable morbidity and mortality in older patients who suffer from COVID-19, many of whom may already have lung disorders (19). Long-term follow-up studies are required to establish the true prevalence of post-COVID-19 fibrosis, but it is speculated that the consequences of COVID-19 could include a large cohort of patients with fibrosis and persistent or progressive lung impairment. Importantly, as thousands of individuals became affected by COVID-19, one can speculate that even rare complications will have major health effects at the population level.
reference link https://www.spandidos-publications.com/10.3892/etm.2020.8980
More information: Christopher Ting et al, Fatal COVID-19 and Non–COVID-19 Acute Respiratory Distress Syndrome Is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State without Fibrosis, The American Journal of Pathology (2021). DOI: 10.1016/j.ajpath.2021.11.014
Thomas R. Martin, Lung Injury and Repair in Coronavirus Disease 2019–Related Acute Lung Injury, The American Journal of Pathology (2022). DOI: 10.1016/j.ajpath.2022.01.001