Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID
Pulmonary fibrosis, severe alveolitis, and the inability to restore alveolar epithelial architecture are primary causes of respiratory failure in fatal COVID-19 cases. However, the factors contributing to abnormal fibrosis in critically ill COVID-19 patients remain unclear. This study analyzed the h...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/14/2/236 |
| _version_ | 1797298781904961536 |
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| author | Teluguakula Narasaraju Indira Neeli Sheila L. Criswell Amita Krishnappa Wenzhao Meng Vasuki Silva Galyna Bila Volodymyr Vovk Zolotukhin Serhiy Gary L. Bowlin Nuala Meyer Eline T. Luning Prak Marko Radic Rostyslav Bilyy |
| author_facet | Teluguakula Narasaraju Indira Neeli Sheila L. Criswell Amita Krishnappa Wenzhao Meng Vasuki Silva Galyna Bila Volodymyr Vovk Zolotukhin Serhiy Gary L. Bowlin Nuala Meyer Eline T. Luning Prak Marko Radic Rostyslav Bilyy |
| author_sort | Teluguakula Narasaraju |
| collection | DOAJ |
| description | Pulmonary fibrosis, severe alveolitis, and the inability to restore alveolar epithelial architecture are primary causes of respiratory failure in fatal COVID-19 cases. However, the factors contributing to abnormal fibrosis in critically ill COVID-19 patients remain unclear. This study analyzed the histopathology of lung specimens from eight COVID-19 and six non-COVID-19 postmortems. We assessed the distribution and changes in extracellular matrix (ECM) proteins, including elastin and collagen, in lung alveoli through morphometric analyses. Our findings reveal the significant degradation of elastin fibers along the thin alveolar walls of the lung parenchyma, a process that precedes the onset of interstitial collagen deposition and widespread intra-alveolar fibrosis. Lungs with collapsed alveoli and organized fibrotic regions showed extensive fragmentation of elastin fibers, accompanied by alveolar epithelial cell death. Immunoblotting of lung autopsy tissue extracts confirmed elastin degradation. Importantly, we found that the loss of elastin was strongly correlated with the induction of neutrophil elastase (NE), a potent protease that degrades ECM. This study affirms the critical role of neutrophils and neutrophil enzymes in the pathogenesis of COVID-19. Consistently, we observed increased staining for peptidyl arginine deiminase, a marker for neutrophil extracellular trap release, and myeloperoxidase, an enzyme-generating reactive oxygen radical, indicating active neutrophil involvement in lung pathology. These findings place neutrophils and elastin degradation at the center of impaired alveolar function and argue that elastolysis and alveolitis trigger abnormal ECM repair and fibrosis in fatal COVID-19 cases. Importantly, this study has implications for severe COVID-19 complications, including long COVID and other chronic inflammatory and fibrotic disorders. |
| first_indexed | 2024-03-07T22:41:02Z |
| format | Article |
| id | doaj.art-c9040d885672481f9ee578e80e3c7ca7 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-07T22:41:02Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-c9040d885672481f9ee578e80e3c7ca72024-02-23T15:09:27ZengMDPI AGBiomolecules2218-273X2024-02-0114223610.3390/biom14020236Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVIDTeluguakula Narasaraju0Indira Neeli1Sheila L. Criswell2Amita Krishnappa3Wenzhao Meng4Vasuki Silva5Galyna Bila6Volodymyr Vovk7Zolotukhin Serhiy8Gary L. Bowlin9Nuala Meyer10Eline T. Luning Prak11Marko Radic12Rostyslav Bilyy13Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Diagnostic and Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Pathology, Adichunchanagiri Institute of Medical Sciences, Adichunchanagiri University, Mandya 571448, IndiaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Histology, Cytology, Histology & Embryology, Danylo Halytsky Lviv National Medical University, 79010 Lviv, UkraineDepartment of Pathological Anatomy and Forensic Medicine, Danylo Halytsky Lviv National Medical University, 79010 Lviv, UkraineLviv Regional Pathological Anatomy Office, CU ENT (Pulmonology Lviv Regional Diagnostic Center), 79000 Lviv, UkraineDepartment of Biomedical Engineering, University of Memphis, Memphis, TN 38152, USAInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Histology, Cytology, Histology & Embryology, Danylo Halytsky Lviv National Medical University, 79010 Lviv, UkrainePulmonary fibrosis, severe alveolitis, and the inability to restore alveolar epithelial architecture are primary causes of respiratory failure in fatal COVID-19 cases. However, the factors contributing to abnormal fibrosis in critically ill COVID-19 patients remain unclear. This study analyzed the histopathology of lung specimens from eight COVID-19 and six non-COVID-19 postmortems. We assessed the distribution and changes in extracellular matrix (ECM) proteins, including elastin and collagen, in lung alveoli through morphometric analyses. Our findings reveal the significant degradation of elastin fibers along the thin alveolar walls of the lung parenchyma, a process that precedes the onset of interstitial collagen deposition and widespread intra-alveolar fibrosis. Lungs with collapsed alveoli and organized fibrotic regions showed extensive fragmentation of elastin fibers, accompanied by alveolar epithelial cell death. Immunoblotting of lung autopsy tissue extracts confirmed elastin degradation. Importantly, we found that the loss of elastin was strongly correlated with the induction of neutrophil elastase (NE), a potent protease that degrades ECM. This study affirms the critical role of neutrophils and neutrophil enzymes in the pathogenesis of COVID-19. Consistently, we observed increased staining for peptidyl arginine deiminase, a marker for neutrophil extracellular trap release, and myeloperoxidase, an enzyme-generating reactive oxygen radical, indicating active neutrophil involvement in lung pathology. These findings place neutrophils and elastin degradation at the center of impaired alveolar function and argue that elastolysis and alveolitis trigger abnormal ECM repair and fibrosis in fatal COVID-19 cases. Importantly, this study has implications for severe COVID-19 complications, including long COVID and other chronic inflammatory and fibrotic disorders.https://www.mdpi.com/2218-273X/14/2/236SARS-CoV-2neutrophil elastaseelastolysisfibrosiscollagenmyeloperoxidase |
| spellingShingle | Teluguakula Narasaraju Indira Neeli Sheila L. Criswell Amita Krishnappa Wenzhao Meng Vasuki Silva Galyna Bila Volodymyr Vovk Zolotukhin Serhiy Gary L. Bowlin Nuala Meyer Eline T. Luning Prak Marko Radic Rostyslav Bilyy Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID Biomolecules SARS-CoV-2 neutrophil elastase elastolysis fibrosis collagen myeloperoxidase |
| title | Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID |
| title_full | Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID |
| title_fullStr | Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID |
| title_full_unstemmed | Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID |
| title_short | Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID |
| title_sort | neutrophil activity and extracellular matrix degradation drivers of lung tissue destruction in fatal covid 19 cases and implications for long covid |
| topic | SARS-CoV-2 neutrophil elastase elastolysis fibrosis collagen myeloperoxidase |
| url | https://www.mdpi.com/2218-273X/14/2/236 |
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