Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantationResearch in context
Soma S.K. Jyothula,
Andrew Peters,
Yafen Liang,
Weizhen Bi,
Pooja Shivshankar,
Simon Yau,
Puneet S. Garcha,
Xiaoyi Yuan,
Bindu Akkanti,
Scott Collum,
Nancy Wareing,
Rajarajan A. Thandavarayan,
Fernando Poli de Frias,
Ivan O. Rosas,
Bihong Zhao,
L. Maximilian Buja,
Holger K. Eltzschig,
Howard J. Huang,
Harry Karmouty-Quintana
Affiliations
Soma S.K. Jyothula
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; Center for Advanced Cardiopulmonary Therapies and Transplantation at UTHealth/McGovern Medical School, Houston, TX, USA
Andrew Peters
Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Yafen Liang
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Weizhen Bi
Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Pooja Shivshankar
Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Simon Yau
Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX, USA
Puneet S. Garcha
Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA
Xiaoyi Yuan
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Bindu Akkanti
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; Center for Advanced Cardiopulmonary Therapies and Transplantation at UTHealth/McGovern Medical School, Houston, TX, USA
Scott Collum
Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Nancy Wareing
Department of Biochemistry and Molecular Biology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Rajarajan A. Thandavarayan
Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX, USA
Fernando Poli de Frias
Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA
Ivan O. Rosas
Department of Medicine, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX, USA
Bihong Zhao
Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
L. Maximilian Buja
Department of Pathology and Laboratory Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Holger K. Eltzschig
Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
Howard J. Huang
Houston Methodist DeBakey Transplant Center, Houston Methodist Hospital, Houston, TX, USA
Harry Karmouty-Quintana
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; Center for Advanced Cardiopulmonary Therapies and Transplantation at UTHealth/McGovern Medical School, Houston, TX, USA; UTHealth Pulmonary Center of Excellence, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; Corresponding author. 6431 Fannin Street, Suite 6.214, Houston, TX 77030.
Summary: 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.
