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Master's Dissertation
DOI
https://doi.org/10.11606/D.17.2022.tde-13072022-145505
Document
Author
Full name
Diego Brito Caetité
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2022
Supervisor
Committee
Alves Filho, José Carlos Farias (President)
Fabro, Alexandre Todorovic
Sousa, Lirlândia Pires de
Title in Portuguese
Participação da anfiregulina (AREG) na fisiopatologia da COVID-19
Keywords in Portuguese
Fibrose
Reparo tecidual
Tolerância
Abstract in Portuguese
Os casos graves de COVID-19 são frequentemente caracterizados por um grande processo inflamatório que pode levar à falência de órgãos e à morte do paciente. Neste contexto, a anfiregulina (AREG), um fator de crescimento epidérmico semelhante ao EGF, tem sido descrita como importante no processo de reparo por exercer um papel fundamental na mediação dos mecanismos de tolerância. Considerando que a AREG é um fator importante no processo de homeostasia durante e após o processo inflamatório, decidimos investigar seu papel na fisiopatologia da COVID-19. Para isso, utilizamos amostras de PBMCs, de autópsias pulmonares e lavado traqueal de pacientes com COVID-19 (leve, moderada e severa) e comparamos a presença de AREG por RT-PCR, imunofluorescência e ELISA com base em grupos controle. Além disso, usamos um modelo experimental de infecção usando como base camundongos K18-hACE2 para entender o papel do AREG na fisiopatologia da COVID-19, também bloqueamos a sinalização do EGFR com intuito entender como os sinais emitidos por esse receptor se relacionam com a doença. Observamos que os níveis de AREG em PBMCs de pacientes com COVID-19 estavam elevados em comparação aos doadores saudáveis e que, este aumento, estava correlacionado com manifestações clínicas mais graves, com um provável desfecho de morte, também observamos um aumento das concentrações de AREG no lavado traqueal de pacientes hospitalizados e no homogenato do pulmão, bem como uma coloração intensa na imunofluorescência de autópsias pulmonares de pacientes que morreram de COVID-19. Vimos também que no modelo experimental de infecção, o AREG estava em altos níveis, assim como outros mediadores inflamatórios. Além disso, o bloqueio da sinalização do receptor AREG melhorou os sinais clínicos da doença no modelo de experimental. Em resumo, nossos dados indicam que o AREG está envolvido no processo fisiopatológico desencadeado pelo SARS-CoV-2 e está relacionado com a gravidade da doença.
Title in English
Role of amphiregulin (AREG) in the pathophysiology of COVID-19
Keywords in English
Fibrosis
Tissue repair
Tolerance
Abstract in English
Severe cases of COVID-19 are often characterized by a large inflammatory process that can lead to organ failure and patient death. In this context, amphiregulin (AREG), an epidermal growth factor EGF-like, has been described as important in the repair process by playing a key role in mediating tolerance mechanisms. Considering that AREG is an important factor in the homeostasis process during and after the inflammatory process, we decided to investigate its role in the pathophysiology of COVID-19. To this end, we used PBMCs, lung autopsy and tracheal lavage samples from patients with COVID-19 (mild, moderate and severe) and compared the presence of AREG by RT-PCR, immunofluorescence and ELISA based on control groups. In addition, we used an experimental infection model using K18-hACE2 mice to understand the role of AREG in the pathophysiology of COVID-19, we also blocked EGFR signaling in order to understand how the signals emitted by this receptor relate to the disease. We observed that AREG levels in PBMCs from patients with COVID-19 were elevated compared to healthy donors, and that this increase correlated with more severe clinical manifestations with a likely outcome of death, we also observed increased AREG concentrations in tracheal lavage from hospitalized patients and in lung homogenate, as well as intense staining in immunofluorescence from lung autopsies of patients who died of COVID-19. We also saw that in the experimental infection model, AREG was at high levels, as were other inflammatory mediators. Furthermore, blocking AREG receptor signaling improved the clinical signs of the disease in the experimental model. In summary, our data indicate that AREG is involved in the pathophysiological process triggered by SARS-CoV-2 and is related to disease severity.
 
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DIEGOBRITOCAETITE.pdf (6.59 Mbytes)
Publishing Date
2022-08-04
 
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