Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation.
Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation.
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DOI：
10.1016/j.ebiom.2022.104351
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发表时间：
2022-12
期刊：
影响因子：
11.1
通讯作者：
Karmouty-Quintanaa, Harry
中科院分区：
文献类型：
--
作者：
Jyothula, Soma S. K.;Peters, Andrew;Liang, Yafen;Bi, Weizhen;Shivshankar, Pooja;Yau, Simon;Garcha, Puneet S.;Yuan, Xiaoyi;Akkanti, Bindu;Collum, Scott;Wareing, Nancy;Thandavarayan, Rajarajan A.;Frias, Fernando Poli de;Rosas, Ivan O.;Zhao, Bihong;Buja, L. Maximilian;Eltzschig, Holger K.;Huang, Howard J.;Karmouty-Quintanaa, Harry
关键词：
冠状病毒病2019(新冠肺炎)可导致急性呼吸窘迫综合征(ARDS)的发展。在一些无法解决的新冠肺炎(NR)患者中，肺损伤可以迅速发展到肺移植是唯一可行的生存选择的程度。这种致命的肺损伤进展包括快速的纤维增生性反应，从最初的症状出现平均需要15周。对于导致NR-新冠肺炎暴发性肺纤维化的机制，我们知之甚少。使用预先设计的无偏聚合酶链式反应阵列检测纤维化标志物，我们分析了NR-新冠肺炎肺的纤维化特征。我们比较了对照肺(供肺移植时被丢弃的肺)和特发性肺纤维化(IPF)患者的移植组织的表达谱。随后，通过RT-qPCR、Western blotts和免疫组织化学的方法验证和定位所选择的促纤维化靶点。共有23个NR-新冠肺炎肺用于RT-qPCR验证。我们揭示了NR-新冠肺炎中一个独特的纤维化基因特征，该特征主要由包括胶原蛋白和Periostin在内的促纤维化基因的过度表达所主导。我们的结果还显示包含1的胶原三螺旋重复序列(CTHRC1)的表达显著增加，该基因共定位于α-平滑肌表达丰富的区域，表示肌成纤维细胞。我们还发现，在成纤维细胞区域和明显的上皮细支气管化区域附近，细胞角蛋白(KRT)5和8的表达细胞显著增加。我们的研究可能对导致NR-新冠肺炎暴发性肺纤维化的潜在细胞机制提供洞察力。美国国立卫生研究院(NIH)授予H.K.E.NIH拨款：R01HL154720、R01DK122796、R01DK109574、R01HL133900和国防部(DoD)拨款W81XWH2110032给H.K.E.NIH授予：R01HL138510和R01HL157100、国防部授予W81XWH-19-1-0007、美国心脏协会授予：18IPA34170220给H.K.-Q.美国心脏协会：19CDA34660279、美国肺脏协会：CA-226265、帕克·B·弗朗西斯奖学金1003167-01以及临床和转化科学中心、麦戈文医学院给X.Y。
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. 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. 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. Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. 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.
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作者：
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影响因子：
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DOI：
10.1183/09031936.00196412
发表时间：
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期刊：
The European respiratory journal
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