tetano
Editor, Senior Moderator
EBioMedicine
. 2022 Nov 11;86:104351.
doi: 10.1016/j.ebiom.2022.104351. Online ahead of print.
Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation
Soma S K Jyothula[SUP] 1 [/SUP], Andrew Peters[SUP] 2 [/SUP], Yafen Liang[SUP] 3 [/SUP], Weizhen Bi[SUP] 2 [/SUP], Pooja Shivshankar[SUP] 2 [/SUP], Simon Yau[SUP] 4 [/SUP], Puneet S Garcha[SUP] 5 [/SUP], Xiaoyi Yuan[SUP] 3 [/SUP], Bindu Akkanti[SUP] 1 [/SUP], Scott Collum[SUP] 2 [/SUP], Nancy Wareing[SUP] 2 [/SUP], Rajarajan A Thandavarayan[SUP] 4 [/SUP], Fernando Poli de Frias[SUP] 5 [/SUP], Ivan O Rosas[SUP] 5 [/SUP], Bihong Zhao[SUP] 6 [/SUP], L Maximilian Buja[SUP] 6 [/SUP], Holger K Eltzschig[SUP] 3 [/SUP], Howard J Huang[SUP] 4 [/SUP], Harry Karmouty-Quintana[SUP] 7 [/SUP]
Affiliations
Abstract
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.
Keywords: CTHRC1; ECMO; Extracellular matrix; Extracorporeal life support; KRT5; KRT8; Periostin (POSTN); Post-acute SARS-CoV-2 sequelae (PASC).
. 2022 Nov 11;86:104351.
doi: 10.1016/j.ebiom.2022.104351. Online ahead of print.
Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation
Soma S K Jyothula[SUP] 1 [/SUP], Andrew Peters[SUP] 2 [/SUP], Yafen Liang[SUP] 3 [/SUP], Weizhen Bi[SUP] 2 [/SUP], Pooja Shivshankar[SUP] 2 [/SUP], Simon Yau[SUP] 4 [/SUP], Puneet S Garcha[SUP] 5 [/SUP], Xiaoyi Yuan[SUP] 3 [/SUP], Bindu Akkanti[SUP] 1 [/SUP], Scott Collum[SUP] 2 [/SUP], Nancy Wareing[SUP] 2 [/SUP], Rajarajan A Thandavarayan[SUP] 4 [/SUP], Fernando Poli de Frias[SUP] 5 [/SUP], Ivan O Rosas[SUP] 5 [/SUP], Bihong Zhao[SUP] 6 [/SUP], L Maximilian Buja[SUP] 6 [/SUP], Holger K Eltzschig[SUP] 3 [/SUP], Howard J Huang[SUP] 4 [/SUP], Harry Karmouty-Quintana[SUP] 7 [/SUP]
Affiliations
- PMID: 36375315
- DOI: 10.1016/j.ebiom.2022.104351
Abstract
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.
Keywords: CTHRC1; ECMO; Extracellular matrix; Extracorporeal life support; KRT5; KRT8; Periostin (POSTN); Post-acute SARS-CoV-2 sequelae (PASC).