%0 Journal Article
%T Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation.
%A Jyothula SSK
%A Peters A
%A Liang Y
%A Bi W
%A Shivshankar P
%A Yau S
%A Garcha PS
%A Yuan X
%A Akkanti B
%A Collum S
%A Wareing N
%A Thandavarayan RA
%A Poli de Frias F
%A Rosas IO
%A Zhao B
%A Buja LM
%A Eltzschig HK
%A Huang HJ
%A Karmouty-Quintana H
%J EBioMedicine
%V 86
%N 0
%D Dec 2022
%M 36375315
%F 11.205
%R 10.1016/j.ebiom.2022.104351
%X <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19.<BR><B>BACKGROUND: </B>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.