Study reveals ferroptosis as a major driver of severe COVID-19 lung damage

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for the coronavirus disease 2019 (COVID-19), has been associated with the manifestation of adverse pulmonary conditions, such as pneumonia and acute respiratory distress syndrome (ARDS). A recent Nature Communications study identifies ferroptosis as a major cell death mechanism underlying COVID-19 lung disease.

Study: Fatal COVID-19 pulmonary disease involves ferroptosis. Image Credit: Mang E / Shutterstock.com Study: Fatal COVID-19 pulmonary disease involves ferroptosis. Image Credit: Mang E / Shutterstock.com

The pulmonary effects of SARS-CoV-2 infection

Both acute and non-acute pulmonary damage have been associated with COVID-19. Severely infected COVID-19 patients often develop ARDS, which accounts for high mortality and poor prognosis.

Lung histology of patients with ARDS has indicated acute lung injury (ALI), particularly diffuse alveolar damage (DAD). The early stage of ARDS has been characterized by edema, hyaline membranes, and fibrosis. Non-acute lung injury (non-ALI) of COVID-19 patients includes microthrombi and pulmonary vascular congestion with hemangiomatosis-like changes. 

COVID-19 pulmonary pathology has been associated with host inflammatory responses, including the cytokine storm and viral infection damage. Chronic immune responses induced by macrophages and neutrophils aggravate pulmonary tissue damage. Furthermore, immune cells lead to a release of reactive oxygen species and free radicals, thereby causing oxidative injury.

Although many supportive treatments, such as mechanical ventilation and intubation, are used to alleviate the pulmonary symptoms of COVID-19, there is no specific cure for this disease. As a result, patients with COVID-19 ARDS are often treated with a combination of anti-inflammatory and anti-viral medications.

In addition to protease inhibitors, immunomodulatory drugs, such as interleukin 6 (IL-6) receptor inhibitors and corticosteroids, have improved survival rates among severely infected patients. Although many studies on COVID-19 have been conducted, additional studies are needed to improve our understanding of the pathogenesis of this disease and ultimately develop targeted and more effective therapeutic strategies.

Ferroptosis is an iron-dependent non-apoptotic form of cell death characterized by extensive peroxidation of phospholipids containing polyunsaturated fatty acyl tails (PL-PUFAs). Lipid peroxidation adversely impacts the cellular repair system, particularly the ferroptosis suppressor protein 1 (FSP1), glutathione peroxidase 4 (GPX4) pathway, and GTP cyclohydrolase 1 (GCH1) pathway, which ultimately leads to cell death.

Previous studies have reported that SARS-CoV-2 infection induces pro-ferroptosis molecular changes, which may lead to ferroptosis in the lungs. Modification of iron homeostasis proteins and accumulation of reactive iron may lead to a disruption of iron metabolism in the lungs. 

About the study

The current study involved the analysis of autopsy samples obtained from patients who died from respiratory failure caused by severe SARS-CoV-2 infection with both ALI and non-ALI pathologies. Mild COVID-19 lung explants were also collected from patients who recovered from the infection.

Control lung samples included resections of pneumothorax lungs and neoplastic lungs, which did not exhibit any signs of SARS-CoV-2 infection or other types of lung injury. Non-COVID-19 control lung autopsies with ALI were also obtained from individuals who died from respiratory failure before the pandemic. Serum samples of all patients were collected to determine ferritin levels. 

Molecular features responsible for pulmonary pathologies in human lung autopsies and a hamster model were evaluated. Mass-spectrometry-based lipidomics was also performed to assess the lipid profile of COVID-19 patient lung autopsies.

Study findings

Post-mortem COVID-19 lung autopsy samples indicated an elevated level of ferroptosis markers, as well as increased iron dysregulation, lipid peroxidation, and lysophospholipids, as well as depletion in PL-PUFAs. 

In both ALI and non-ALI fatal COVID-19 lung samples, a significant increase in ferroptosis features was observed. Blood accumulation was observed in lung parenchyma, which indicates intracerebral hemorrhage due to ferroptosis. Dead blood cells release cytotoxic agents and iron into the adjacent cells, which increases inflammation and tissue damage.

Consistent with previous research, the current study reports the presence of high serum ferritin and ferritin light chain in the lung tissue of severe COVID-19 samples. Iron-rich extracellular vesicles secreted by ferroptotic cells, including macrophages, spread cell-death signals to their surroundings and increase tissue damage.

Mechanistically, ferric ammonium citrate (FAC) activates lipid peroxidation in primary lung epithelial cells, which was suppressed by ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1.

Lipidomics analysis revealed a significant depletion of PL-PUFAs, dipalmitoyl-phosphatidylcholine, and palmitoyl-oleoyl-PG, as well as an accumulation of lysophospholipids in severe COVID-19 lungs. These could be attributed to the formation of hyaline membranes in COVID-19 ALI.

A Syrian hamster model of COVID-19 revealed a robust correlation between ferroptosis markers (TfR1) and the lipid peroxidation product 4 hydroxynonenal-4-HNE with lung injury severity.

Conclusions

The current study identified ferroptosis as a key cell death mechanism associated with COVID-19 lung disease. Analysis of human COVID-19 lung tissue exhibited unique molecular features of ferroptosis in severe lung pathologies. This observation was supported by the Syrian hamster model of SARS-CoV-2 infection, which highlighted an association of ferroptosis with lung pathology.

Considering the role of ferroptosis in the lung pathology of SARS-CoV-2 infection, therapeutics capable of suppressing iron-dependent cell death could be effective in treating severe COVID-19.

Journal reference:
  • Qiu, B., Zandkarimi, F., Saqi, A., et al. (2024) Fatal COVID-19 pulmonary disease involves ferroptosis. Nature Communications 15(1); 1-13. doi:10.1038/s41467-024-48055-0
Dr. Priyom Bose

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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