TY - JOUR
T1 - Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation
AU - Jyothula, Soma S.K.
AU - Peters, Andrew
AU - Liang, Yafen
AU - Bi, Weizhen
AU - Shivshankar, Pooja
AU - Yau, Simon
AU - Garcha, Puneet S.
AU - Yuan, Xiaoyi
AU - Akkanti, Bindu
AU - Collum, Scott
AU - Wareing, Nancy
AU - Thandavarayan, Rajarajan A.
AU - Poli de Frias, Fernando
AU - Rosas, Ivan O.
AU - Zhao, Bihong
AU - Buja, L. Maximilian
AU - Eltzschig, Holger K.
AU - Huang, Howard J.
AU - Karmouty-Quintana, Harry
N1 - Funding Information:
Kelli Wallen (MPH), for her help in proof-reading the manuscript. National Institutes of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DOD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167–01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.
Funding Information:
Kelli Wallen (MPH), for her help in proof-reading the manuscript. National Institutes of Health (NIH) Grants R01HL154720 , R01DK122796 , R01DK109574 , R01HL133900 , and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100 , DOD Grant W81XWH-19-1-0007 , and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association : 19CDA34660279 , American Lung Association : CA-622265 , Parker B. Francis Fellowship , 1UL1TR003167–01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/12
Y1 - 2022/12
N2 - Background: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19. Methods: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation. Findings: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization. Interpretation: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. Funding: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167–01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.
AB - Background: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19. Methods: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation. Findings: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization. Interpretation: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. Funding: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167–01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.
KW - CTHRC1
KW - ECMO
KW - Extracellular matrix
KW - Extracorporeal life support
KW - KRT5
KW - KRT8
KW - Periostin (POSTN)
KW - Post-acute SARS-CoV-2 sequelae (PASC)
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U2 - 10.1016/j.ebiom.2022.104351
DO - 10.1016/j.ebiom.2022.104351
M3 - Article
C2 - 36375315
SN - 2352-3964
VL - 86
SP - 104351
JO - EBioMedicine
JF - EBioMedicine
M1 - 104351
ER -